Testing random effects in linear mixed‐effects models with serially correlated errors

In linear mixed-effects models, random effects are used to capture the heterogeneityand variability between individuals due to unmeasured covariates or unknown bio-logical differences. Testing for the need of random effects is a nonstandard problembecause it requires testing on the boundary of parameter space where the asymptoticchi-squared distribution of the classical tests such as likelihood ratio and score testsis incorrect. In the literature several tests have been proposed to overcome this diffi-culty, however all of these tests rely on the restrictive assumption of i.i.d. measurementerrors. The presence of correlated errors, which often happens in practice, makes test-ing random effects much more difficult. In this paper, we propose a permutation testfor random effects in the presence of serially correlated errors. The proposed test notonly avoids issues with the boundary of parameter space, but also can be used fortesting multiple random effects and any subset of them. Our permutation procedureincludes the permutation procedure in Drikvandi, Verbeke, Khodadadi, and PartoviNia (2013) as a special case when errors are i.i.d., though the test statistics are dif-ferent. We use simulations and a real data analysis to evaluate the performance of theproposed permutation test. We have found that random slopes for linear and quadratictime effects may not be significant when measurement errors are serially correlated

The impact of slow steaming on refrigerated exports from New Zealand

The practice of slow steaming has had a significant impact on New Zealand export industries with increased transit times in some cases causing significant reductions in shelf life once the product has reached the retail stage. The longer transit times also impose the extra cost to exporters of having more inventory tied up in transit. While there is clear evidence to suggest slow steaming has reduced fuel consumption and hence fuel emissions and fuel costs, these savings have not been passed on by the liners to their customers. However, there is no indication that slow-steaming has caused a significant reduction in export earnings for New Zealand (at least up to the middle of 2014). A predicted move to super-slow steaming would put extra strain on the New Zealand meat industry especially, with their lucrative European chilled lamb market under particular threat

Alemtuzumab-induced halo nevus-like hypopigmentation – New insights into secondary skin autoimmunity in response to an immune cell-depleting antibody

We describe a 33‐year‐old male patient who developed hypopigmentation around his melanocytic nevi with disappearance of the nevi in August 2018. In June 2016 he had been diagnosed with highly active RRMS and treated with alemtuzumab in September 2016 for the first time. In September 2017 another cycle of alemtuzumab was administered. The patient’s family history for vitiligo was unremarkable and he had no autoimmune thyroid disease

Direct and indirect contacts between cattle farms in north-west England

Little is known regarding the types and frequencies of contact that exist between farms and which of these may act as pathogen transmission routes; however it is likely that farms demonstrate considerable heterogeneity in such contacts. In this cross-sectional study, we explored the direct and indirect contact types and frequencies that exist between cattle farms within a region, focusing on potential routes of pathogen transmission. The owners/managers of 56 farms located in a 10 km by 10 km study area in north-west England were administered an interview-based questionnaire between June and September 2005. Information was obtained relating to contact types and frequencies, including those involving animal movements, equipment sharing between farms and any contractors or companies visiting the farms. The data was explored using hierarchical cluster analysis and network analysis. There was considerable variation between farms arising from different contact types. Some networks exhibited great connectivity, incorporating approximately 90% of the farms interviewed in a single component, whilst other networks were more fragmented, with multiple small components (sets of connected farms not linked with other farms). A range of factors influencing contact between farms were identified. For example, contiguous farms were more likely to be linked via other contacts, such as sharing of equipment and direct farm-to-farm animal movements (p < 0.001 and p = 0.02, respectively). The frequency of contacts was also investigated; it is likely that the amount of contact a farm receives from a company or contractor and whether or not biosecurity is performed after contact would impact on disease transmission potential. We found considerable heterogeneity in contact frequency and that many company and contractor personnel undertook little biosecurity. These findings lead to greater understanding of inter-farm contact and may aid development of appropriate biosecurity practices and control procedures, and inform mathematical modelling of infectious diseases

The frequency of transforming growth factor-TGF-B gene polymorphisms in a normal southern Iranian population

Several single nucleotide polymorphisms (SNPs) of the transforming growth factor-β1 gene (TGFB1) have been reported. Determination of TGFB1 SNPs allele frequencies in different ethnic groups is useful for both population genetic analyses and association studies with immunological diseases. In this study, five SNPs of TGFB1 were determined in 325 individuals from a normal southern Iranian population using polymerase chain reaction-restriction fragment length polymorphism method. This population was in Hardy-Weinberg equilibrium for these SNPs. Of the 12 constructed haplotypes, GTCGC and GCTGC were the most frequent in the normal southern Iranian population. Comparison of genotype and allele frequencies of TGFB SNPs between Iranian and other populations (meta-analysis) showed significant differences, and in this case the southern Iranian population seems genetically similar to Caucasoid populations. However, neighbour-joining tree using Nei's genetic distances based on TGF-β1 allele frequencies showed that southern Iranians are genetically far from people from the USA, Germany, UK, Denmark and the Czech Republic. In conclusion, this is the first report of the distribution of TGFB1 SNPs in an Iranian population and the results of this investigation may provide useful information for both population genetic and disease studies. © 2008 The Authors

Immunophenotypic analysis reveals differences in circulating immune cells in the peripheral blood of patients with segmental and nonsegmental vitiligo

Accumulating studies have indicated immune-based destruction of melanocytes in both segmental vitiligo (SV) and non-SV (NSV). Whereas SV often occurs unilaterally during childhood and stabilizes after an initial period of activity, the disease course of NSV is usually slowly progressive, with new lesions occurring bilaterally during life. This suggests an involvement of distinct pathophysiology pathways, specifically increased systemic immune activation in patients with NSV but not in patients with SV. This research aimed to identify the differences in immune cells in the blood of patients with SV and NSV through immunophenotyping of circulating cells. Regulatory T cells were unaffected in patients with SV compared with that in healthy controls but decreased in patients with NSV. In patients with NSV, the reduction in regulatory T cells was associated with the presence of other systemic autoimmune comorbidities, which were less present in SV. Similarly, the absence of a melanocyte-specific antibody response in patients with SV suggests less involvement of B-cell immunity in SV. These data show that in contrast to patients with NSV, no increased systemic immunity is found in patients with SV, indicating that SV pathogenesis is associated with a localized cytotoxic reaction targeting epidermal melanocytes

Popular attitudes to memory, the body, and social identity : the rise of external commemoration in Britain, Ireland, and New England

A comparative analysis of samples of external memorials from burial grounds in Britain, Ireland and New England reveals a widespread pattern of change in monument style and content, and exponential growth in the number of permanent memorials from the 18th century onwards. Although manifested in regionally distinctive styles on which most academic attention has so far been directed, the expansion reflects global changes in social relationships and concepts of memory and the body. An archaeological perspective reveals the importance of external memorials in articulating these changing attitudes in a world of increasing material consumption

Numerical comparison of two approaches for the study of phase transitions in small systems

We compare two recently proposed methods for the characterization of phase transitions in small systems. The validity and usefulness of these approaches are studied for the case of the q=4 and q=5 Potts model, i.e. systems where a thermodynamic limit and exact results exist. Guided by this analysis we discuss then the helix-coil transition in polyalanine, an example of structural transitions in biological molecules.Comment: 16 pages and 7 figure

Anti-Melanoma immunity and local regression of cutaneous metastases in melanoma patients treated with monobenzone and imiquimod; a phase 2 a trial

Vitiligo development in melanoma patients during immunotherapy is a favorable prognostic sign and indicates breakage of tolerance against melanocytic/melanoma antigens. We investigated a novel immunotherapeutic approach of the skin-depigmenting compound monobenzone synergizing with imiquimod in inducing antimelanoma immunity and melanoma regression. Stage III-IV melanoma patients with non-resectable cutaneous melanoma metastases were treated with monobenzone and imiquimod (MI) therapy applied locally to cutaneous metastases and adjacent skin during 12 weeks, or longer. Twenty-one of 25 enrolled patients were evaluable for clinical assessment at 12 weeks. MI therapy was well-tolerated. Partial regression of cutaneous metastases was observed in 8 patients and stable disease in 1 patient, reaching the statistical endpoint of treatment efficacy. Continued treatment induced clinical response in 11 patients, including complete responses in three patients. Seven patients developed vitiligo-like depigmentation on areas of skin that were not treated with MI therapy, indicating a systemic effect of MI therapy. Melanoma-specific antibody responses were induced in 7 of 17 patients tested and melanoma-specific CD8+T-cell responses in 11 of 15 patients tested. These systemic immune responses were significantly increased during therapy as compared to baseline in responding patients. This study shows that MI therapy induces local and systemic anti-melanoma immunity and local regression of cutaneous metastases in 38% of patients, or 52% during prolonged therapy. This study provides proof-of-concept of MI therapy, a low-cost, broadly applicable and well-tolerated treatment for cutaneous melanoma metastases, attractive for further clinical investigation

Genome-wide association analyses identify 13 new susceptibility loci for generalized vitiligo

We previously reported a genome-wide association study (GWAS) identifying 14 susceptibility loci for generalized vitiligo. We report here a second GWAS (450 individuals with vitiligo (cases) and 3,182 controls), an independent replication study (1,440 cases and 1,316 controls) and a meta-analysis (3,187 cases and 6,723 controls) identifying 13 additional vitiligo-associated loci. These include OCA2-HERC2 (combined P = 3.80 × 10 ), MC1R (P = 1.82 × 10 ), a region near TYR (P = 1.57 × 10 ), IFIH1 (P = 4.91 × 10 ), CD80 (P = 3.78 × 10 ), CLNK (P = 1.56 × 10 ), BACH2 (P = 2.53 × 10 ), SLA (P = 1.58 × 10 ), CASP7 (P = 3.56 × 10 ), CD44 (P = 1.78 × 10 ), IKZF4 (P = 2.75 × 10 ), SH2B3 (P = 3.54 × 10 ) and TOB2 (P = 6.81 × 10 ). Most vitiligo susceptibility loci encode immunoregulatory proteins or melanocyte components that likely mediate immune targeting and the relationships among vitiligo, melanoma, and eye, skin and hair coloration