A comparison of block and semi-parametric bootstrap methods for variance estimation in spatial statistics

Efron (1979) introduced the bootstrap method for independent data but it cannot be easily applied to spatial data because of their dependency. For spatial data that are correlated in terms of their locations in the underlying space the moving block bootstrap method is usually used to estimate the precision measures of the estimators. The precision of the moving block bootstrap estimators is related to the block size which is difficult to select. In the moving block bootstrap method also the variance estimator is underestimated. In this paper, first the semi-parametric bootstrap is used to estimate the precision measures of estimators in spatial data analysis. In the semi-parametric bootstrap method, we use the estimation of the spatial correlation structure. Then, we compare the semi-parametric bootstrap with a moving block bootstrap for variance estimation of estimators in a simulation study. Finally, we use the semi-parametric bootstrap to analyze the coal-ash data

Dyskinesias after neural transplantation in Parkinson's disease: what do we know and what is next?

Since the 1980 s, when cell transplantation into the brain as a cure for Parkinson's disease hit the headlines, several patients with Parkinson's disease have received transplantation of cells from aborted fetuses with the aim of replacing the dopamine cells destroyed by the disease. The results in human studies were unpredictable and raised controversy. Some patients showed remarkable improvement, but many of the patients who underwent transplantation experienced serious disabling adverse reactions, putting an end to human trials since the late 1990 s. These side effects consisted of patients' developing troublesome involuntary, uncontrolled movements in the absence of dopaminergic medication, so-called off-phase, graft-induced dyskinesias. Notwithstanding the several mechanisms having been proposed, the pathogenesis of this type of dyskinesias remained unclear and there was no effective treatment. It has been suggested that graft-induced dyskinesias could be related to fiber outgrowth from the graft causing increased dopamine release, that could be related to the failure of grafts to restore a precise distribution of dopaminergic synaptic contacts on host neurons or may also be induced by inflammatory and immune responses around the graft. A recent study, however, hypothesized that an important factor for the development of graft-induced dyskinesias could include the composition of the cell suspension and specifically that a high proportion of serotonergic neurons cografted in these transplants engage in nonphysiological properties such as false transmitter release. The findings from this study showed serotonergic hyperinnervation in the grafted striatum of two patients with Parkinson's disease who exhibited major motor recovery after transplantation with fetal mesencephalic tissue but later developed graft-induced dyskinesias. Moreover, the dyskinesias were significantly attenuated by administration of a serotonin agonist, which activates the inhibitory serotonin autoreceptors and attenuates transmitter release from serotonergic neurons, indicating that graft-induced dyskinesias were caused by the dense serotonergic innervation engaging in false transmitter release. Here the implications of the recent findings for the development of new human trials testing the safety and efficacy of cell transplantation in patients with Parkinson's disease are discussed

Cholinergic imaging in dementia spectrum disorders

The multifaceted nature of the pathology of dementia spectrum disorders has complicated their management and the development of effective treatments. This is despite the fact that they are far from uncommon, with Alzheimer’s disease (AD) alone affecting 35 million people worldwide. The cholinergic system has been found to be crucially involved in cognitive function, with cholinergic dysfunction playing a pivotal role in the pathophysiology of dementia. The use of molecular imaging such as SPECT and PET for tagging targets within the cholinergic system has shown promise for elucidating key aspects of underlying pathology in dementia spectrum disorders, including AD or parkinsonian dementias. SPECT and PET studies using selective radioligands for cholinergic markers, such as [(11)C]MP4A and [(11)C]PMP PET for acetylcholinesterase (AChE), [(123)I]5IA SPECT for the α(4)β(2) nicotinic acetylcholine receptor and [(123)I]IBVM SPECT for the vesicular acetylcholine transporter, have been developed in an attempt to clarify those aspects of the diseases that remain unclear. This has led to a variety of findings, such as cortical AChE being significantly reduced in Parkinson’s disease (PD), PD with dementia (PDD) and AD, as well as correlating with certain aspects of cognitive function such as attention and working memory. Thalamic AChE is significantly reduced in progressive supranuclear palsy (PSP) and multiple system atrophy, whilst it is not affected in PD. Some of these findings have brought about suggestions for the improvement of clinical practice, such as the use of a thalamic/cortical AChE ratio to differentiate between PD and PSP, two diseases that could overlap in terms of initial clinical presentation. Here, we review the findings from molecular imaging studies that have investigated the role of the cholinergic system in dementia spectrum disorders

Deuteros 2.0: Peptide-level significance testing of data from hydrogen deuterium exchange mass spectrometry

Summary: Hydrogen deuterium exchange mass spectrometry (HDX-MS) is becoming increasing routine for monitoring changes in the structural dynamics of proteins. Differential HDX-MS allows comparison of individual protein states, such as in the absence or presence of a ligand. This can be used to attribute changes in conformation to binding events, allowing the mapping of entire con-formational networks. As such, the number of necessary cross-state comparisons quickly increas-es as additional states are introduced to the system of study. There are currently very few software packages available that offer quick and informative comparison of HDX-MS datasets and even few-er which offer statistical analysis and advanced visualization. Following the feedback from our origi-nal software Deuteros, we present Deuteros 2.0 which has been redesigned from the ground up to fulfil a greater role in the HDX-MS analysis pipeline. Deuteros 2.0 features a repertoire of facilities for back exchange correction, data summarization, peptide-level statistical analysis and advanced data plotting features. Availability: Deuteros 2.0 can be downloaded from https://github.com/andymlau/Deuteros_2.0 under the Apache 2.0 license. Installation of Deuteros 2.0 requires the MATLAB Runtime Library available free of charge from MathWorks (https://www.mathworks.com/products/compiler/matlab-runtime.html) and is available for both Windows and Mac operating systems.Comment: Application note with 3 pages, 1 figur

Specification testing when the null is nonparametric or semiparametric.

This paper discusses the problem of testing misspecifications in semiparametric regression models for a large family of econometric models under rather general conditions. We focus on two main issues that typically arise in econometrics. First, many econometric models are estimated through maximum likelihood or pseudoML methods like, for example, limited dependent variable or gravity models. Second, often one might not want to fully specify the null hypothesis. Instead, one would rather impose some structure like separability or monotonicity. In order to address these points we introduce an adaptive omnibus test. Special emphasis is given to practical issues like adaptive bandwidth choice, general but simple requirements on the estimates, and finite sample performance, including the resampling approximations.We acknowledge nancial support from FUNCAS, the Spanish Projects MTM2008-03010 and ECO2010-15455, and the DAAD Project 50119348

Genetics of Late-Onset Alzheimer's Disease: Update from the Alzgene Database and Analysis of Shared Pathways

The genetics of late-onset Alzheimer's disease (LOAD) has taken impressive steps forwards in the last few years. To date, more than six-hundred genes have been linked to the disorder. However, only a minority of them are supported by a sufficient level of evidence. This review focused on such genes and analyzed shared biological pathways. Genetic markers were selected from a web-based collection (Alzgene). For each SNP in the database, it was possible to perform a meta-analysis. The quality of studies was assessed using criteria such as size of research samples, heterogeneity across studies, and protection from publication bias. This produced a list of 15 top-rated genes: APOE, CLU, PICALM, EXOC3L2, BIN1, CR1, SORL1, TNK1, IL8, LDLR, CST3, CHRNB2, SORCS1, TNF, and CCR2. A systematic analysis of gene ontology terms associated with each marker showed that most genes were implicated in cholesterol metabolism, intracellular transport of beta-amyloid precursor, and autophagy of damaged organelles. Moreover, the impact of these genes on complement cascade and cytokine production highlights the role of inflammatory response in AD pathogenesis. Gene-gene and gene-environment interactions are prominent issues in AD genetics, but they are not specifically featured in the Alzgene database