2,484 research outputs found
A one-way ANOVA test for functional data with graphical interpretation
A new functional ANOVA test, with a graphical interpretation of the result,
is presented. The test is an extension of the global envelope test introduced
by Myllymaki et al. (2017, Global envelope tests for spatial processes, J. R.
Statist. Soc. B 79, 381--404, doi: 10.1111/rssb.12172). The graphical
interpretation is realized by a global envelope which is drawn jointly for all
samples of functions. If a mean function computed from the empirical data is
out of the given envelope, the null hypothesis is rejected with the
predetermined significance level . The advantages of the proposed
one-way functional ANOVA are that it identifies the domains of the functions
which are responsible for the potential rejection. We introduce two versions of
this test: the first gives a graphical interpretation of the test results in
the original space of the functions and the second immediately offers a
post-hoc test by identifying the significant pair-wise differences between
groups. The proposed tests rely on discretization of the functions, therefore
the tests are also applicable in the multidimensional ANOVA problem. In the
empirical part of the article, we demonstrate the use of the method by
analyzing fiscal decentralization in European countries. The aim of the
empirical analysis is to capture differences between the levels of government
expenditure decentralization ratio among different groups of European
countries. The idea behind, based on the existing literature, is
straightforward: countries with a longer European integration history are
supposed to decentralize more of their government expenditure. We use the
government expenditure centralization ratios of 29 European Union and EFTA
countries in period from 1995 to 2016 sorted into three groups according to the
presumed level of European economic and political integration.Comment: arXiv admin note: text overlap with arXiv:1506.0164
Eine "low-cost" WĂ€rmebildkamera zum selber bauen
Eine WĂ€rmebildkamera bietet aus didaktischer Perspektive interessante
Möglichkeiten, viele Aspekte der WÀrmelehre und eine breite Palette
alltagsbezogener Kontexte auf eine völlig neue Weise experimentell zu
untersuchen. Sie âmisstâ die Temperatur eines Objektes nicht wie ein
Thermometer, sondern registriert die ausgesendete elektromagnetische Strahlung
in einem bestimmten infraroten Spektralbereich, die sogenannte WĂ€rmestrahlung.
Die Interpretation der so generierten âWĂ€rmebilderâ in Form von
Falschfarbendarstellungen erlaubt dann Aussagen zum Temperaturprofil. DarĂŒber
hinaus erweisen sich die farbigen WÀrmebilder als Àsthetisch sehr ansprechend.
Obwohl professionelle WĂ€rmebildkameras in den letzten Jahren deutlich
preiswerter geworden sind, zÀhlen sie noch lange nicht zur Standardausstattung
einer physikalischen Schulsammlung, und eine Anschaffung sprengt derzeit noch
(fast) jeden Physiketat. Um die zukĂŒnftige breitere Implementierung dieser
Technik im Physikunterricht zu unterstĂŒtzen, sollen in diesem Beitrag
Anregungen fĂŒr den Selbstbau einer âlow-costâ WĂ€rmebildkamera gegeben und
mögliche Anwendungsmöglichkeiten anhand von (einfachen) Versuchen mit einer
solchen sehr preiswerten Alternative aufgezeigt werden. Auch mit dieser Kamera
gelingt es, bislang âUnsichtbaresâ â die WĂ€rmestrahlung â sichtbar zu machen
Supreme Court Amicus Brief Regarding Wyeth v. Diana Levine
Prominent in arguments opposing preemption of state tort law liability for alleged inadequacies in prescription drug labeling is the argument that such liability can complement FDA regulation by improving on a regulatory scheme that fails to provide adequate deterrence against the marketing of unsafe or inadequately labeled drugs. The premise of this argument is faulty. Fundamental principles of economics and numerous studies of FDA drug regulation reveal that FDA in fact errs on the side of overregulation of prescription drugs. Product liability litigation focused solely on one side of the prescription drug public health equation leads to further distortions of the drug approval and labeling process and exacerbates FDA's inherent overly cautious approach. Preemption of state tort law where it conflicts with FDA requirements will minimize these distortions and thereby maximize public health.Health and Safety, Other Topics
Building community - or why we need on ongoing conference platform for TA
As a background for current outlooks towards strengthening the technology assessment (TA) community, Scherz et al. give a historical overview of efforts to establish international fora for communication among professionals and researchers in TA. Against this background, the article conveys experiences from the first two bi-annual TA conferences, arranged in the context of the PACITA project. The authors describe experiences of mutual learning across national boundaries and communicate a renewed understanding of the necessity for supporting TA capacities at the national level through professional community building. Ultimately, Scherz et al. argue that a European TA platform is necessary for establishing a common language for TA and for supporting the spread of TA across borders
Genomic structure of the horse major histocompatibility complex class II region resolved using PacBio long-read sequencing technology
The mammalian Major Histocompatibility Complex (MHC) region contains several gene families characterized by highly polymorphic loci with extensive nucleotide diversity, copy number variation of paralogous genes, and long repetitive sequences. This structural complexity has made it difficult to construct a reliable reference sequence of the horse MHC region. In this study, we used long-read single molecule, real-time (SMRT) sequencing technology from Pacific Biosciences (PacBio) to sequence eight Bacterial Artificial Chromosome (BAC) clones spanning the horse MHC class II region. The final assembly resulted in a 1,165,328âbp continuous gap free sequence with 35 manually curated genomic loci of which 23 were considered to be functional and 12 to be pseudogenes. In comparison to the MHC class II region in other mammals, the corresponding region in horse shows extraordinary copy number variation and different relative location and directionality of the Eqca-DRB, -DQA, -DQB and âDOB loci. This is the first long-read sequence assembly of the horse MHC class II region with rigorous manual gene annotation, and it will serve as an important resource for association studies of immune-mediated equine diseases and for evolutionary analysis of genetic diversity in this region
Human herpesvirus 6A and axonal injury before the clinical onset of multiple sclerosis
Recent research indicates that multiple sclerosis is preceded by a prodromal phase with elevated levels of serum neurofilament light chain (sNfL), a marker of axonal injury. The effect of environmental risk factors on the extent of axonal injury during this prodrome is unknown. Human herpesvirus 6A (HHV-6A) is associated with an increased risk of developing multiple sclerosis. The objective of this study was to determine if HHV-6A serostatus is associated with the level of sNfL in the multiple sclerosis prodrome, which would support a causative role of HHV-6A. A nested case-control study was performed by crosslinking multiple sclerosis registries with Swedish biobanks. Individuals with biobank samples collected before the clinical onset of multiple sclerosis were included as cases. Controls without multiple sclerosis were randomly selected, matched for biobank, sex, sampling date and age. Serostatus of HHV-6A and Epstein-Barr virus (EBV) was analysed with a bead-based multiplex assay. The concentration of sNfL was analysed with Single molecule array technology. The association between HHV-6A serology and sNfL was assessed by stratified t-tests and linear regressions, adjusted for EBV serostatus and sampling age. Within-pair ratios of HHV-6A seroreactivity and sNfL were calculated for each case and its matched control. To assess the temporal relationship between HHV-6A antibodies and sNfL, these ratios were plotted against the time to the clinical onset of multiple sclerosis and compared using locally estimated scatterplot smoothing regressions with 95% confidence intervals (CI). Samples from 519 matched case-control pairs were included. In cases, seropositivity of HHV-6A was significantly associated with the level of sNfL (+11%, 95% CI 0.2-24%, Pâ=â0.045), and most pronounced in the younger half of the cases (+24%, 95% CI 6-45%, Pâ=â0.007). No such associations were observed among the controls. Increasing seroreactivity against HHV-6A was detectable before the rise of sNfL (significant within-pair ratios from 13.6 years vs 6.6 years before the clinical onset of multiple sclerosis). In this study, we describe the association between HHV-6A antibodies and the degree of axonal injury in the multiple sclerosis prodrome. The findings indicate that elevated HHV-6A antibodies both precede and are associated with a higher degree of axonal injury, supporting the hypothesis that HHV-6A infection may contribute to multiple sclerosis development in a proportion of cases
Efficacy and safety of N-acetyl-l-leucine in NiemannâPick disease type C
Objective: To investigate the safety and efficacy of N-acetyl-L-leucine (NALL) on symptoms, functioning, and quality of life in pediatric (â„ 6 years) and adult Niemann-Pick disease type C (NPC) patients. Methods: In this multi-national, open-label, rater-blinded Phase II study, patients were assessed during a baseline period, a 6-week treatment period (orally administered NALL 4 g/day in patients â„ 13 years, weight-tiered doses for patients 6-12 years), and a 6-week post-treatment washout period. The primary Clinical Impression of Change in Severity (CI-CS) endpoint (based on a 7-point Likert scale) was assessed by blinded, centralized raters who compared randomized video pairs of each patient performing a pre-defined primary anchor test (8-Meter Walk Test or 9-Hole Peg Test) during each study periods. Secondary outcomes included cerebellar functional rating scales, clinical global impression, and quality of life assessments. Results: 33 subjects aged 7-64 years with a confirmed diagnosis of NPC were enrolled. 32 patients were included in the primary modified intention-to-treat analysis. NALL met the CI-CS primary endpoint (mean difference 0.86, SD = 2.52, 90% CI 0.25, 1.75, p = 0.029), as well as secondary endpoints. No treatment-related serious adverse events occurred. Conclusions: NALL demonstrated a statistically significant and clinical meaningfully improvement in symptoms, functioning, and quality of life in 6 weeks, the clinical effect of which was lost after the 6-week washout period. NALL was safe and well-tolerated, informing a favorable benefit-risk profile for the treatment of NPC. CLINICALTRIALS. Gov identifier: NCT03759639
Treatment- and population-specific genetic risk factors for anti-drug antibodies against interferon-beta: a GWAS
BackgroundUpon treatment with biopharmaceuticals, the immune system may produce anti-drug antibodies (ADA) that inhibit the therapy. Up to 40% of multiple sclerosis patients treated with interferon beta (IFN beta) develop ADA, for which a genetic predisposition exists. Here, we present a genome-wide association study on ADA and predict the occurrence of antibodies in multiple sclerosis patients treated with different interferon beta preparations.MethodsWe analyzed a large sample of 2757 genotyped and imputed patients from two cohorts (Sweden and Germany), split between a discovery and a replication dataset. Binding ADA (bADA) levels were measured by capture-ELISA, neutralizing ADA (nADA) titers using a bioassay. Genome-wide association analyses were conducted stratified by cohort and treatment preparation, followed by fixed-effects meta-analysis.ResultsBinding ADA levels and nADA titers were correlated and showed a significant heritability (47% and 50%, respectively). The risk factors differed strongly by treatment preparation: The top-associated and replicated variants for nADA presence were the HLA-associated variants rs77278603 in IFN beta -1a s.c.- (odds ratio (OR)=3.55 (95% confidence interval=2.81-4.48), p=2.1x10(-26)) and rs28366299 in IFN beta -1b s.c.-treated patients (OR=3.56 (2.69-4.72), p=6.6x10(-19)). The rs77278603-correlated HLA haplotype DR15-DQ6 conferred risk specifically for IFN beta -1a s.c. (OR=2.88 (2.29-3.61), p=7.4x10(-20)) while DR3-DQ2 was protective (OR=0.37 (0.27-0.52), p=3.7x10(-09)). The haplotype DR4-DQ3 was the major risk haplotype for IFN beta -1b s.c. (OR=7.35 (4.33-12.47), p=1.5x10(-13)). These haplotypes exhibit large population-specific frequency differences. The best prediction models were achieved for ADA in IFN beta -1a s.c.-treated patients. Here, the prediction in the Swedish cohort showed AUC=0.91 (0.85-0.95), sensitivity=0.78, and specificity=0.90;patients with the top 30% of genetic risk had, compared to patients in the bottom 30%, an OR =73.9 (11.8-463.6, p=4.4x10(-6)) of developing nADA. In the German cohort, the AUC of the same model was 0.83 (0.71-0.92), sensitivity=0.80, specificity=0.76, with an OR=13.8 (3.0-63.3, p=7.5x10(-4)).ConclusionsWe identified several HLA-associated genetic risk factors for ADA against interferon beta, which were specific for treatment preparations and population backgrounds. Genetic prediction models could robustly identify patients at risk for developing ADA and might be used for personalized therapy recommendations and stratified ADA screening in clinical practice. These analyses serve as a roadmap for genetic characterizations of ADA against other biopharmaceutical compounds
Importance of Human Leukocyte Antigen (HLA) Class I and II Alleles on the Risk of Multiple Sclerosis
Multiple sclerosis (MS) is a complex disease of the central nervous system of unknown etiology. The human leukocyte antigen (HLA) locus on chromosome 6 confers a considerable part of the susceptibility to MS, and the most important factor is the class II allele HLA-DRB1*15:01. In addition, we and others have previously established a protective effect of HLA-A*02. Here, we genotyped 1,784 patients and 1,660 healthy controls from Scandinavia for the HLA-A, HLA-B, HLA-C and HLA-DRB1 genes and investigated their effects on MS risk by logistic regression. Several allele groups were found to exert effects independently of DRB1*15 and A*02, in particular DRB1*01 (ORâ=â0.82, pâ=â0.034) and B*12 (including B*44/45, ORâ=â0.76, pâ=â0.0028), confirming previous reports. Furthermore, we observed interaction between allele groups: DRB1*15 and DRB1*01 (multiplicative: ORâ=â0.54, pâ=â0.0041; additive: APâ=â0.47, pâ=â4Ă10â06), DRB1*15 and C*12 (multiplicative: ORâ=â0.37, pâ=â0.00035; additive: APâ=â0.58, pâ=â2.6Ă10â05), indicating that the effect size of these allele groups varies when taking DRB1*15 into account. Analysis of inferred haplotypes showed that almost all DRB1*15 bearing haplotypes were risk haplotypes, and that all A*02 bearing haplotypes were protective as long as they did not carry DRB1*15. In contrast, we found one class I haplotype, carrying A*02-C*05-B*12, which abolished the risk of DRB1*15. In conclusion, these results confirms a complex role of HLA class I and II genes that goes beyond DRB1*15 and A*02, in particular by including all three classical HLA class I genes as well as functional interactions between DRB1*15 and several alleles of DRB1 and class I genes
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