Areawise significance tests for windowed recurrence network analysis.
ABSTRACT: Many time-series analysis techniques use sliding window approaches or are repeatedly applied over a continuous range of parameters. When combined with a significance test, intrinsic correlations among the pointwise analysis results can make falsely positive significant points appear as continuous patches rather than as isolated points. To account for this effect, we present an areawise significance test that identifies such false-positive patches. For this purpose, we numerically estimate the decorrelation length of the statistic of interest by calculating correlation functions between the analysis results and require an areawise significant point to belong to a patch of pointwise significant points that is larger than this decorrelation length. We apply our areawise test to results from windowed traditional and scale-specific recurrence network analysis in order to identify dynamical anomalies in time series of a non-stationary Rössler system and tree ring width index values from Eastern Canada. Especially, in the palaeoclimate context, the areawise testing approach markedly reduces the number of points that are identified as significant and therefore highlights only the most relevant features in the data. This provides a crucial step towards further establishing recurrence networks as a tool for palaeoclimate data analysis.
Project description:We present integrated Laser Speckle Contrast Imaging (LSCI) and Sidestream Dark Field (SDF) flowmetry to provide real-time, non-invasive and quantitative measurements of speckle decorrelation times related to microcirculatory flow. Using a multi exposure acquisition scheme, precise speckle decorrelation times were obtained. Applying SDF-LSCI in vitro and in vivo allows direct comparison between speckle contrast decorrelation and flow velocities, while imaging the phantom and microcirculation architecture. This resulted in a novel analysis approach that distinguishes decorrelation due to flow from other additive decorrelation sources.
Project description:The Idiopathic Intracranial Hypertension Treatment Trial (IIHTT) showed that acetazolamide provided a modest, significant improvement in mean deviation (MD). Here, we further analyze visual field changes over the 6-month study period.Of 165 subjects with mild visual loss in the IIHTT, 125 had perimetry at baseline and 6 months. We evaluated pointwise linear regression of visual sensitivity versus time to classify test locations in the worst MD (study) eye as improving or not; pointwise changes from baseline to month 6 in decibels; and clinical consensus of change from baseline to 6 months.The average study eye had 36 of 52 test locations with improving sensitivity over 6 months using pointwise linear regression, but differences between the acetazolamide and placebo groups were not significant. Pointwise results mostly improved in both treatment groups with the magnitude of the mean change within groups greatest and statistically significant around the blind spot and the nasal area, especially in the acetazolamide group. The consensus classification of visual field change from baseline to 6 months in the study eye yielded percentages (acetazolamide, placebo) of 7.2% and 17.5% worse, 35.1% and 31.7% with no change, and 56.1% and 50.8% improved; group differences were not statistically significant.In the IIHTT, compared to the placebo group, the acetazolamide group had a significant pointwise improvement in visual field function, particularly in the nasal and pericecal areas; the latter is likely due to reduction in blind spot size related to improvement in papilledema. (ClinicalTrials.gov number, NCT01003639.).
Project description:The ability of a neuronal population to effectuate channel decorrelation, which is one form of response decorrelation, has been identified as an essential prelude to efficient neural encoding. To what extent are diverse forms of local and afferent heterogeneities essential in accomplishing channel decorrelation in the dentate gyrus (DG)? Here, we incrementally incorporated four distinct forms of biological heterogeneities into conductance-based network models of the DG and systematically delineate their relative contributions to channel decorrelation. First, to effectively incorporate intrinsic heterogeneities, we built physiologically validated heterogeneous populations of granule (GC) and basket cells (BC) through independent stochastic search algorithms spanning exhaustive parametric spaces. These stochastic search algorithms, which were independently constrained by experimentally determined ion channels and by neurophysiological signatures, revealed cellular-scale degeneracy in the DG. Specifically, in GC and BC populations, disparate parametric combinations yielded similar physiological signatures, with underlying parameters exhibiting significant variability and weak pair-wise correlations. Second, we introduced synaptic heterogeneities through randomization of local synaptic strengths. Third, in including adult neurogenesis, we subjected the valid model populations to randomized structural plasticity and matched neuronal excitability to electrophysiological data. We assessed networks comprising different combinations of these three local heterogeneities with identical or heterogeneous afferent inputs from the entorhinal cortex. We found that the three forms of local heterogeneities were independently and synergistically capable of mediating significant channel decorrelation when the network was driven by identical afferent inputs. However, when we incorporated afferent heterogeneities into the network to account for the divergence in DG afferent connectivity, the impact of all three forms of local heterogeneities was significantly suppressed by the dominant role of afferent heterogeneities in mediating channel decorrelation. Our results unveil a unique convergence of cellular- and network-scale degeneracy in the emergence of channel decorrelation in the DG, whereby disparate forms of local and afferent heterogeneities could synergistically drive input discriminability.
Project description:Millennial-scale palaeoclimate variability has been documented in various terrestrial and marine palaeoclimate proxy records throughout the Northern Hemisphere for the last glacial cycle. Its clear expression and rapid shifts between different states of climate (Greenland Interstadials and Stadials) represents a correlation tool beyond the resolution of e.g. luminescence dating, especially relevant for terrestrial deposits. Usually, comparison of terrestrial proxy datasets and the Greenland ice cores indicates a complex expression of millennial-scale climate variability as recorded in terrestrial geoarchives including loess. Loess is the most widespread terrestrial geoarchive of the Quaternary and especially widespread over Eurasia. However, loess often records a smoothed representation of millennial-scale variability without all fidelity when compared to the Greenland data, this being a relevant limiting feature in integrating loess with other palaeoclimate records. To better understand the loess proxy-response to millennial-scale climate variability, we simulate a proxy signal smoothing by natural processes through application of low-pass filters of ?18O data from Greenland, a high-resolution palaeoclimate reference record, alongside speleothem isotope records from the Black Sea-Mediterranean region. We show that low-pass filters represent rather simple models for better constraining the expression of millennial-scale climate variability in low sedimentation environments, and in sediments where proxy-response signals are most likely affected by natural smoothing (by e.g. bioturbation). Interestingly, smoothed datasets from Greenland and the Black Sea-Mediterranean region are most similar in the last ~15 ka and between ~50-30 ka. Between ~30-15 ka, roughly corresponding to the Last Glacial Maximum and the deglaciation, the records show dissimilarities, challenging the construction of robust correlative time-scales in this age range. From our analysis it becomes apparent that patterns of palaeoclimate signals in loess-palaeosol sequences often might be better explained by smoothed Greenland reference data than the original high-resolution Greenland dataset, or other reference data. This opens the possibility to better assess the temporal resolution and palaeoclimate potential of loess-palaeosol sequences in recording supra-regional climate patterns, as well as to securely integrate loess with other chronologically better-resolved palaeoclimate records.
Project description:Pointwise localization of individual fluorophores is a critical step in super-resolution localization microscopy and single particle tracking. Although the methods are limited by the localization errors of individual fluorophores, the pointwise localization precision has so far been estimated using theoretical best case approximations that disregard, for example, motion blur, defocus effects and variations in fluorescence intensity. Here, we show that pointwise localization precision can be accurately estimated directly from imaging data using the Bayesian posterior density constrained by simple microscope properties. We further demonstrate that the estimated localization precision can be used to improve downstream quantitative analysis, such as estimation of diffusion constants and detection of changes in molecular motion patterns. Finally, the quality of actual point localizations in live cell super-resolution microscopy can be improved beyond the information theoretic lower bound for localization errors in individual images, by modelling the movement of fluorophores and accounting for their pointwise localization uncertainty.
Project description:Quantitative blood flow measurements using optical coherence tomography (OCT) have a wide potential range of medical research and clinical applications. Flowmetry based on the temporal dynamics of the OCT signal may have the ability to measure three-dimensional flow profiles regardless of the flow direction. State-of-the-art models describing the OCT signal temporal statistics are based on dynamic light scattering (DLS), a model which is inherently limited to single scattering regimes. DLS methods continue to be applied to OCT despite the knowledge that red blood cells produce strong forward multiple scattering. Here, we postulate that forward multiple scattering is the primary mechanism causing the rate of speckle-decorrelation derived from data acquired in vivo to deviate from the rate of decorrelation determined in phantom experiments. We also postulate that multiple scattering contributions to decorrelation are only present when the sample exhibits velocity field inhomogeneities larger than the scale of a resolution volume and are thus absent in rigid bulk motion. To test these hypotheses, we performed a systematic study of the effects of forward multiple scattering on OCT signal decorrelation with phantom experiments under physiologically relevant flow conditions and relative bulk motion. Our experimental results confirm that the amount of forward multiple scattering affects the proportionality between lateral flow and decorrelation. We propose that multiply scattered light carries information from different locations in the sample and each location imprints scattering dynamics on the scattered light causing increased decorrelation rates. Our analysis confirms that the detection of forward scattered light inside the vessel lumen causes an increase in the rate of decorrelation which results in an overestimation of blood flow velocities at depths as shallow as 40 µm into whole blood for OCT systems with typical numerical apertures used in retinal imaging.
Project description:Bortezomib induced peripheral neuropathy is a dose-limiting side effect and a major concern in the treatment of multiple myeloma. To identify genetic risk factors associated with the development of this side effect in bortezomib treated multiple myeloma patients, a pharmacogenetic association study was performed using a discovery set (IFM 2005-01; n = 238) and a validation set (HOVON65/GMMG-HD4 and a Czech dataset; n = 231). After multiplicity correction, none of the 2,149 single nucleotide polymorphisms tested revealed any significant association with bortezomib induced peripheral neuropathy. However, 56 single nucleotide polymorphisms demonstrated an association with bortezomib induced peripheral neuropathy with pointwise, uncorrected significance. Pathway analysis of these polymorphisms demonstrated involvement of neurological disease (FDR <20%). Also a clear enrichment of major bortezomib metabolizing genes was found. Univariate evaluation of these 56 polymorphisms in the validation set demonstrated one single nucleotide polymorphism with pointwise significance: rs619824 in CYP17A1. (IFM 2005-01 clinicaltrials.gov identifier: NCT00200681; HOVON-65/GMMG-HD4 isrctn.org identifier: ISRCTN64455289).
Project description:PURPOSE:A previous study of Old Order Amish families showed an association of ocular refraction with markers proximal to matrix metalloproteinase (MMP) genes MMP1 and MMP10 and intragenic to MMP2. A candidate gene replication study of association between refraction and single nucleotide polymorphisms (SNPs) within these genomic regions was conducted. DESIGN:Candidate gene genetic association study. PARTICIPANTS:Two thousand participants drawn from the Age-Related Eye Disease Study (AREDS) were chosen for genotyping. After quality-control filtering, 1912 individuals were available for analysis. METHODS:Microarray genotyping was performed using the HumanOmni 2.5 bead array (Illumina, Inc., San Diego, CA). Single nucleotide polymorphisms originally typed in the previous Amish association study were extracted for analysis. In addition, haplotype tagging SNPs were genotyped using TaqMan assays. Quantitative trait association analyses of mean spherical equivalent refraction were performed on 30 markers using linear regression models and an additive genetic risk model while adjusting for age, sex, education, and population substructure. Post hoc analyses were performed after stratifying on a dichotomous education variable. Pointwise (P(emp)) and multiple-test study-wise (P(multi)) significance levels were calculated empirically through permutation. MAIN OUTCOME MEASURES:Mean spherical equivalent refraction was used as a quantitative measure of ocular refraction. RESULTS:The mean age and ocular refraction were 68 years (standard deviation [SD], 4.7 years) and +0.55 diopters (D; SD, 2.14 D), respectively. Pointwise statistical significance was obtained for rs1939008 (P(emp) = 0.0326). No SNP attained statistical significance after correcting for multiple testing. In stratified analyses, multiple SNPs reached pointwise significance in the lower-education group: 2 of these were statistically significant after multiple testing correction. The 2 highest-ranking SNPs in Amish families (rs1939008 and rs9928731) showed pointwise P(emp)<0.01 in the lower-education stratum of AREDS participants. CONCLUSIONS:This study showed suggestive evidence of replication of an association signal for ocular refraction to a marker between MMP1 and MMP10. Evidence of a gene-environment interaction between previously reported markers and education on refractive error also was shown. Variants in MMP1 through MMP10 and MMP2 regions seem to affect population variation in ocular refraction in environmental conditions less favorable for myopia development.
Project description:The nucleus basalis of the basal forebrain is an essential component of the neuromodulatory system controlling the behavioral state of an animal and it is thought to be important in regulating arousal and attention. However, the effect of nucleus basalis activation on sensory processing remains poorly understood. Using polytrode recording in rat visual cortex, we found that nucleus basalis stimulation caused prominent decorrelation between neurons and marked improvement in the reliability of neuronal responses to natural scenes. The decorrelation depended on local activation of cortical muscarinic acetylcholine receptors, whereas the increased reliability involved distributed neural circuits, as evidenced by nucleus basalis-induced changes in thalamic responses. Further analysis showed that the decorrelation and increased reliability improved cortical representation of natural stimuli in a complementary manner. Thus, the basal forebrain neuromodulatory circuit, which is known to be activated during aroused and attentive states, acts through both local and distributed mechanisms to improve sensory coding.
Project description:Red blood cells (RBCs) undergo irreversible biochemical and morphological changes during storage, contributing to the hemorheological changes of stored RBCs, which causes deterioration of microvascular perfusion in vivo. In this study, a home-built optofluidic system for laser speckle imaging of flowing stored RBCs through a transparent microfluidic channel was employed. The speckle decorrelation time (SDT) provides a quantitative measure of RBC changes, including aggregation in the microchannel. The SDT and relative light transmission intensity of the stored RBCs were monitored for 42 days. In addition, correlations between the decorrelation time, RBC flow speed through the channel, and relative light transmission intensity were obtained. The SDT of stored RBCs increased as the storage duration increased. The SDTs of the RBCs stored for 21 days did not significantly change. However, for the RBCs stored for over 35 days, the SDT increased significantly from 1.26 ± 0.27 ms to 6.12 ± 1.98 ms. In addition, we measured the relative light transmission intensity and RBC flow speed. As the RBC storage time increased, the relative light transmission intensity increased, whereas the RBC flow speed decreased in the microchannel. The optofluidic laser speckle image decorrelation time provides a quantitative measure of assessing the RBC condition during storage. Laser speckle image decorrelation analysis may serve as a convenient assay to monitor the property changes of stored RBCs.