Individual Slopes Research Articles

Trajectories of physiological dysregulation predicts mortality and health outcomes in a consistent manner across three populations

Mechanistic and evolutionary perspectives both agree that aging involves multiple integrated biochemical networks in the organism. In particular, the homeostatic physiological dysregulation (PD) hypothesis contends that aging is caused by the progressive breakdown of key regulatory processes. However, nothing is yet known about the specifics of how PD changes with age and affects health. Using a recently validated measure of PD involving the calculation of a multivariate distance (DM) from biomarker data, we show that PD trajectories predict mortality, frailty, and chronic diseases (cancer, cardiovascular diseases, and diabetes). Specifically, relative risks of outcomes associated with individual slopes in (i.e. rate of) dysregulation range 1.20–1.40 per unit slope. We confirm the results by replicating the analysis using two suites of biomarkers selected with markedly different criteria and, for mortality, in three longitudinal cohort-based studies. Overall, the consistence of effect sizes (direction and magnitude) across data sets, biomarker suites and outcomes suggests that the positive relationship between DM and health outcomes is a general phenomenon found across human populations. Therefore, the study of dysregulation trajectories should allow important insights into aging physiology and provide clinically meaningful predictors of outcomes.

Multifield coupled quintessence

We study models of quintessence consisting of a number of scalar fields coupled to several dark matter components. In the case of exponential potentials the scaling solutions can be described in terms of a single field. The corresponding effective logarithmic slope and effective coupling can be written in a simple form in terms of the individual slopes and couplings of the original fields. We also investigate solutions where the scalar potential is negligible, in particular those leading to transient matter dominated solutions. Finally, we compute the evolution equations for the linear perturbations which will allow these models to be tested against current and future observational data.

Multi-trait linear reaction norm model to describe the pattern of phenotypic expression of some economic traits in beef cattle across a range of environments.

The multi-trait reaction norm (MTRN) model was extended to beef cattle reared under tropical conditions with the following objectives: to compare multi-trait (MT) and MTRN models regarding the genetic parameters obtained; and to characterize G × E, the pattern of phenotypic expression, and the environmental sensitivity of animals for postweaning weight gain (PWG), scrotal circumference (SC), and annual average productivity of the cow (PRODAM). There was divergence in the estimates between the MT and MTRN models when the posterior probability intervals of additive genetic variances and heritability coefficients of PWG and PRODAM were analyzed. The MTRN model indicated an increase in heritability for PWG and PRODAM with improvement of the environmental conditions. For SC, heritability was practically the same, irrespective of the environmental conditions. The genetic correlations between the traits studied were low but varied over environments by the MTRN model. Considering genetic correlations obtained by the MTRN model for the same trait, lower estimates were obtained between extreme favorable and unfavorable environments. This finding suggest re-ranking of breeding values in different environments mainly for PWG and PRODAM. Thus, G × E is more important for PWG and PRODAM than for SC and should be included in the genetic evaluation of these traits. The traits PWG and PRODAM can be considered plastic traits, whereas SC is poorly plastic. The genetic trends in individual animal slopes indicate that the population is moving towards greater plasticity. This could be a matter of concern for breeders since greater plasticity seems to limit heritability and, consequently, the responses to selection.

A new geotechnical method for natural slope exploration and analysis

Geotechnical investigation of natural slopes is challengeable especially when natural slopes having higher gradients and access is difficult. Also, it is even more prob- lematic to find the shear strength parameters spatially to evaluate the stability of slopes as most of the methods available to find the shear strength parameters in the literature are uneconomical or such methods cannot be applied in vegetated slopes. Recently, authors have conducted a series of in situ investigations based on the newly developed lightweight dynamic cone penetrometer to examine its applicability in analyzing the slopes covered with weathering remnants of decomposed granite. Six patterns were identified based on the penetration resistance varies with the depth. Spatial variability analysis conducted on different grid spaces showed that the coefficient of variation of cone resistance varies from 0 to 35 %. Semi-variogram analysis showed that the Spherical Models can be used to evaluate the spatial variability of weathering remnants of decomposed granite. A series of laboratory calibration tests based on the lightweight dynamic cone penetration tests and direct shear tests with pore pressure measurements were conducted at different void ratios and degrees of saturation. Based on the laboratory calibration test results, a method to determine the void ratio, e, from the data of qd was presented. Based on this, two formulas to evaluate the shear strength parameters, apparent cohesion and friction angle, were established with the cone resistance and degree of saturation. Slight modification was proposed in evaluating the apparent cohesion with respect to the different fine content in the soils. As a whole, the proposed method can be successfully applied to individual slopes to determine the profile thickness and to evaluate the shear strength parameters spatially. Based on this, hazard assessment of individual slopes can be made.

Energy approach to seismically induced slope failure and its application to case histories — Supplement

In the previous paper, an energy approach was applied to actual cases of seismically induced slope failures to back-calculated mobilized friction coefficients using gross earthquake energies at individual slopes. In this supplement, based on an observation in a simple shaking table test, the earthquake energy, not the gross energy but a part of it driving soil mass in downslope direction has been identified, and employed to reevaluate individual slopes using nearby acceleration records. It has been found that the reevaluation decreased the earthquake energy to a quarter of the gross value on average. Accordingly, it has significantly reduced the back-calculated friction coefficients for natural slopes and manmade fill slopes for small volume failures in particular, though correlations of the friction coefficient with pertinent parameters for slope failures are qualitatively unaltered.

Individual landslide hazard assessment of natural valleys and slopes based on geotechnical investigation and analysis

Slope failures caused by rainfall on weathered granite are common occurrences in many parts of the world and it is more severe in Japan where there are a significant number of slopes susceptible to failure. At present, about 31,987 natural, and valley slopes are found to be susceptible to landslide disasters in Hiroshima Prefecture, the highest number of any prefecture in Japan. In Hiroshima Prefecture, the prefectural land is divided into 350 units of 5km2, and the hazard of each unit was assessed based on the rainfall data and past records of failures. However, the existing hazard assessment system was found not to be adequate of making better predictions of individual failures in the region, and moreover the system was developed without carrying out any reliable slope stability analyses. In this study, an attempt has been made to understand the mechanism of individual slope failure through seepage analyses and stability analyses. A series of laboratory model tests were conducted to develop the relationships among volumetric water content, degree of saturation, suction, and coefficient of hydraulic conductivity under unsaturated conditions. Field investigation and laboratory tests were conducted based on the four valleys which were identified as potentially hazardous zones in Higashi-Hiroshima city in Hiroshima Prefecture. Graphical relationships were developed among the volumetric water content, suction, rainfall intensity, coefficient of hydraulic conductivity, and degree of saturation for Masado soils. Based on the relationships developed, suction was calculated along the soil profile of natural valleys with the lapse of time. Thus, shear strength parameters were determined based on the degree of saturation calculated from the data of volumetric water contents. The stability analyses revealed that the factor of safety gradually decreases with the formation of High Moisture Content Belt (HMCB) and drastically reduces with the formation of the water table. The susceptibility of failure for each of the four valleys is given based on the hazard assessment system, and is compared and discussed.

Measuring spatial effects in the presence of institutional constraints: The case of Italian Local Health Authority expenditure

Over the last decades spatial econometric models have represented a common tool for measuring spillover effects across different geographical entities (counties, provinces, regions or nations). The aim of this paper is to investigate the issue of measuring spatial spillovers in the presence of institutional constraints that can be geographically defined. In these cases, assuming that spatial effects are not affected by the institutional setting may produce biased estimates due to the composition of twodistinct sources of spatial dependence. Our approach is based on redefining the contiguity structure so as to account for the institutional constraints using two different contiguity matrices: the within matrix, which defines contiguity among units obeying the same institutional setting, and the between matrix, which traces spatial linkages among contiguous units across different jurisdictions. This approach allows to disentangle the two sources of spatial correlation and to easily test for the existence of binding institutional constraints. From the econometric perspective, we extend Lacombe (2004) approach to incorporate the aforementioned institutional constraints in a spatial Durbin model with individual specific slopes, while inference is conducted using a two-way cluster robust variance–covariance matrix controlling for both spatial and time correlations. We apply this methodology to analyze spatial dependence of per-capita public health expenditures in Italyat Local Health Authority level using a balanced panel dataset from 2001 to 2005. Our results show robust evidence of a significant and positive spatial coefficient for the within effect, while the between effect, although significant, is very close to zero, thus confirming the importance and validity of the proposed approach.

Natural environment of MIS 5 and soil catena sequence along a loess slope in the Seret River valley: Evidence from the Pronyatyn Palaeolithic site (Ukraine)

The Middle Palaeolithic site in Pronyatyn village is situated on the Ternopil Plateau, on the eastern, long and straight slope of the Krucha Gora hill (369.5 m a.s.l.). The structure of loess cover in this area was investigated in the series of archaeological excavations to a depth of 5–6 m in 1977–1985, 2010 and 2011. Lithological, palaeomagnetical and palynological analyses, as well as TL dating were carried out in the selected profiles. In all profiles, under thin cover of loess from the last aeolian deposition sub-cycle (MIS 2), a set of soils of S1 = Gorohiv s.l.; (MIS 5 complex) exists. This complex is composed of interglacial and interstadial units. Forest and forest-steppe vegetation, followed by a rich steppe with the continuous occurrence of trees and shrubs and without subarctic elements, developed during the stages of its formation. Based on the investigations of loess cover carried out over a large area, it was found that all sequences are spatially diversified in the profiles located along and across the slope in the middle part of this area. This diversity resulted from the development of pedogenetic and slope processes, depending on morphological features of individual slope segments. In the southern part of the study area, outside the extent of artifact occurrence, the deposits representing MIS 5 are undisturbed or slightly disturbed and contain a loess-soil sequence, which is composed of the interglacial Cambisol (with evidence for the Blake palaeomagnetic event) and 2–3 interstadial soils. Artifacts were discovered in the northern and northwestern parts of the study area, within a solifluctionally redeposited chernozem occurring on a denuded Luvisol. Based on the analysis of the artifact collection, the flint industry is the Western-Podolian, Levallois, radial-parallel, flakes-and-blades, without two-sided tools and with domination of knife-like products on Levallois blanks. This suggestion of the flint industry age as within the younger part of MIS 5 is supported by TL dates. It is most possible that this settlement took place in MIS 5c. Based on spatial distribution of artifacts, state of their preservation, and the features of solifluction deposits representing the younger part of MIS 5, we conclude that the site was originally located on the slope above the excavation area, about 30–50 m to the west.

Reductions in central venous pressure by lower body negative pressure or blood loss elicit similar hemodynamic responses.

The purpose of this study was to compare hemodynamic and blood analyte responses to reduced central venous pressure (CVP) and pulse pressure (PP) elicited during graded lower body negative pressure (LBNP) to those observed during graded blood loss (BL) in conscious humans. We hypothesized that the stimulus-response relationships of CVP and PP to hemodynamic responses during LBNP would mimic those observed during BL. We assessed CVP, PP, heart rate, mean arterial pressure (MAP), and other hemodynamic markers in 12 men during LBNP and BL. Blood samples were obtained for analysis of catecholamines, hematocrit, hemoglobin, arginine vasopressin, and blood gases. LBNP consisted of 5-min stages at 0, 15, 30, and 45 mmHg of suction. BL consisted of 5 min at baseline and following three stages of 333 ml of hemorrhage (1,000 ml total). Individual r(2) values and linear regression slopes were calculated to determine whether the stimulus (CVP and PP)-hemodynamic response trajectories were similar between protocols. The CVP-MAP trajectory was the only CVP-response slope that was statistically different during LBNP compared with BL (0.93 ± 0.27 vs. 0.13 ± 0.26; P = 0.037). The PP-heart rate trajectory was the only PP-response slope that was statistically different during LBNP compared with BL (-1.85 ± 0.45 vs. -0.46 ± 0.27; P = 0.024). Norepinephrine, hematocrit, and hemoglobin were all lower at termination in the BL protocol compared with LBNP (P < 0.05). Consistent with our hypothesis, LBNP mimics the hemodynamic stimulus-response trajectories observed during BL across a significant range of CVP in humans.

Analyzing acute procedural pain in clinical trials

Because acute procedural pain tends to increase with procedure time, assessments of pain management strategies must take that time relationship into account. Statistical time-course analyses are, however, complex and require large patient numbers to detect differences. The current study evaluated the abilities of various single and simple composite measures such as averaged pain or individual patient pain slopes to detect treatment effects. Secondary analyses were performed with the data from 3 prospective randomized clinical trials that assessed the effect of a self-hypnotic relaxation intervention on procedural pain, measured every 10–15minutes during vascular/renal interventions, breast biopsies, and tumor embolizations. Single point-in-time and maximal pain comparisons were poor in detecting treatment effects. Linear data sets of individual patient slopes yielded the same qualitative results as the more complex repeated measures analyses, allowing the use of standard statistical approaches (eg, Kruskal-Wallis), and promising analyses of smaller subgroups, which otherwise would be underpowered. With nonlinear data, a simple averaged score was highly sensitive in detecting differences. Use of these 2 workable and relatively simple approaches may be a first step towards facilitating the development of data sets that could enable meta-analyses of data from acute pain trials.

Catecholamine responses to central hypovolemia induced by lower body negative pressure and blood loss in humans (707.2)

We tested the hypothesis that the catecholamine response would be similar during lower body negative pressure (LBNP) vs. blood loss (BL). Twelve men underwent randomized LBNP and BL protocols on the same day. LBNP consisted of 5‐minute stages at 0, ‐15, ‐30, and ‐45 mmHg of pressure. The BL protocol included 5 minutes at baseline and then after three stages of 333 ml of whole blood draws (1000 ml total) which were stored for reinfusion. Central venous pressure (CVP) was recorded during each protocol. Blood samples were collected at baseline and at the end of the last stage of each protocol. CVP was greater in LBNP vs. BL at baseline (7.3 ± 0.6 vs. 6.1 ± 0.6 mmHg; P &lt; 0.01) and was lower during LBNP vs. BL (‐0.2 ± 0.6 vs. 1.8 ± 0.8 mmHg; P &lt; 0.01). The increase in epinephrine (EPI) during LBNP (53 ± 7 vs.144 ± 30 pg/ml) and BL (49 ± 7 vs. 103 ± 19 pg/ml; P &lt; 0.01) was similar (P = 0.16). An increase in norepinephrine (NE) during LBNP (148 ± 20 vs. 354 ± 44 pg/ml; P &lt; 0.01) was greater (P &lt; 0.01) than the trend to increase during BL (155 ± 22 vs. 211 ± 29 pg/ml; P = 0.09). Individual slopes of catecholamines vs. CVP were calculated to determine if the responses had similar trajectories between the two protocols. The EPI vs. CVP slope was steeper in LBNP vs. BL (‐13.5 ± 4.6 vs. ‐0.6 ± 0.1 pg/ml/mmHg; P &lt; 0.01). The NE vs. CVP slope was steeper in LBNP vs. BL (‐27.8 ± 5.6 vs. ‐8.7 ± 5.9 pg/ml/mmHg; P = 0.01). LBNP to ‐45 mmHg appears to be a greater sympathetic stressor than 1000 ml of BL.Grant Funding Source: Supported by US Army MRMC Combat Casualty Care Research Program Grant # W81XWH‐11‐1‐0823

Muscle Heat Shock Protein 70 Predicts Insulin Resistance With Aging

Heat shock protein 70 (HSP70) protects cells from accumulating damaged proteins and age-related functional decline. We studied plasma and skeletal muscle (SkM) HSP70 levels in adult vervet monkeys (life span ≈ 25 years) at baseline and after 4 years (≈10 human years). Insulin, glucose, homeostasis model assessment scores, triglycerides, high-density lipoprotein and total plasma cholesterol, body weight, body mass index, and waist circumference were measured repeatedly, with change over time estimated by individual regression slopes. Low baseline SkM HSP70 was a proximal marker for developing insulin resistance and was seen in monkeys whose insulin and homeostasis model assessment increased more rapidly over time. Changes in SkM HSP70 inversely correlated with insulin and homeostasis model assessment trajectories such that a positive change in SkM level was beneficial. The strength of the relationship between changes in SkM HSP70 and insulin remained unchanged after adjustment for all covariates. Younger monkeys drove these relationships, with HSP70 alone being predictive of insulin changes with aging. Plasma and SkM HSP70 were unrelated and HSP70 release from peripheral blood mononuclear cells was positively associated with insulin concentrations in contrast to SkM. Results from aged humans confirmed this positive association of plasma HSP70 and insulin. In conclusion, higher levels of SkM HSP70 protect against insulin resistance development during healthy aging.

The triple oxygen isotope composition of the Earth mantle and understanding [formula omitted] variations in terrestrial rocks and minerals

It has been shown in numerous studies that terrestrial rocks and minerals fall on a line with slope ∼0.52 in a δO17 vs. δO18 diagram. In this study, we present new data on the triple isotope composition of the Earth mantle, crustal materials and low-T aqueous precipitates. Crustal materials show distinct variations in ΔO17 suggesting that the concept of a single terrestrial mass fractionation is invalid on small-scale. Observable variations in individual fractionation slopes θ are interpreted as temperature effects. We show that the Earth mantle is isotopically homogeneous and confirm the recent finding that the Earth mantle has a negative ΔO17. The difference in δO18 and ΔO17 between seawater and oceanic crust is discussed with respect to the effects of low- and high-temperature water–rock interaction.

A Joint Modeling Approach for Right Censored High Dimensional Multivariate Longitudinal Data.

Analysis of multivariate longitudinal data becomes complicated when the outcomes are of high dimension and informative right censoring is prevailing. Here, we propose a likelihood based approach for high dimensional outcomes wherein we jointly model the censoring process along with the slopes of the multivariate outcomes in the same likelihood function. We utilized pseudo likelihood function to generate parameter estimates for the population slopes and Empirical Bayes estimates for the individual slopes. The proposed approach was applied to jointly model longitudinal measures of blood urea nitrogen, plasma creatinine, and estimated glomerular filtration rate which are key markers of kidney function in a cohort of renal transplant patients followed from kidney transplant to kidney failure. Feasibility of the proposed joint model for high dimensional multivariate outcomes was successfully demonstrated and its performance was compared to that of a pairwise bivariate model. Our simulation study results suggested that there was a significant reduction in bias and mean squared errors associated with the joint model compared to the pairwise bivariate model.

Changes in the body posture of women occurring with age

BackgroundA current topic in the field of geriatrics still needing a great deal of study is the changes in body posture occurring with age. Symptoms of these changes can be observed starting between the ages of 40–50 years with a slow progression that increases after 60 years of age. The aims of this study were to evaluate parameters characterizing the posture of women over the age of 60 years compared with a control group and to determine the dynamics of body posture changes in the following decades.MethodsThe study included 260 randomly selected women. The study group consisted of 130 women between the ages of 60–90 years (Older Women). The control group (Younger Women) consisted of 130 women between the ages of 20–25 years (posture stabilization period). The photogrammetric method was used to evaluate body posture using the phenomenon of the projection chamber. The study was conducted according to generally accepted principles.ResultsIn the analysis of parameters characterizing individual slope curves, results were varied among different age groups. The lumbar spine slope did not show significant differences between different age groups (p = 0.6952), while statistically significant differences (p = 0.0000) were found in the thoracic-lumbar spine slope (p = 0.0033) and upper thoracic spine slope. Body angle was shown to increase with age (p = 0.0000). Thoracic kyphosis depth significantly deepened with age (p = 0.0002), however, the thoracic kyphosis angle decreased with age (p = 0.0000). An increase in asymmetries was noticed, provided by a significantly higher angle of the shoulder line (p = 0.0199) and the difference in height of the lower shoulder blade angle (p = 0.0007) measurements in the group of older women.ConclusionsChanges in the parameters describing body posture throughout consecutive decades were observed. Therapy for women over the age of 60 years should involve strengthening of the erector spinae muscles and controlling body posture with the aim of reducing trunk inclination and deepening of thoracic kyphosis. Moreover, exercises shaping lumbar lordosis should be performed to prevent its flattening.

Easy methods for extracting individual regression slopes: Comparing SPSS, R, and Excel

An increasingly popular analysis of within-subjects designs revolves around regression coefficients that are estimated individually for each participant. More precisely, a dependent variable (criterion) is regressed on an independent variable (predictor) individually for each participant. The extracted values for slopes and intercept are then compared between conditions or tested against a population value of 0 via standard significance tests such as paired-samples t-tests or repeated-measures analyses of variance (ANOVA). This procedure is commonly known as regression coefficient analysis (RCA; Lorch & Myers, 1990, Method 3). RCA circumvents methodological problems of standard regression analysis which assumes different observations to be independent from each other. This assumption is routinely violated by data from within-subjects designs, but it does not apply to the coefficients that were extracted from individual data sets (cf. Lorch & Myers, 1990). In contrast, RCA only assumes a linear relationship between predictor and criterion for each individual participant and can be used for both, continuous and dichotomous predictors (Ahn, Jung, & Kang, 2002; Lorch & Myers, 1990; Myers & Broyles,

One Year Follow-up of Functional Recovery in Neovascular AMD During Monthly Anti-VEGF Treatment

To identify neurosensory recovery, testing different functional variables during monthly intravitreal standard anti-vascular endothelial growth factor (VEGF) therapy in neovascular age-related macular degeneration (AMD). Prospective interventional cohort study. Sixty-four treatment-naïve neovascular AMD patients with subfoveal lesions were treated and examined monthly for distance visual acuity, reading acuity, maximum reading speed, and contrast sensitivity and with microperimetry evaluating the percentage of absolute and relative scotoma and mean central retinal sensitivity weighted by area. Improvements in reading acuity, distance acuity, reading speed, contrast sensitivity, mean central retinal sensitivity, and scotoma area in dependence of age, lesion type, lesion size, and mean central retinal sensitivity were evaluated by a random-slope and random-intercept model. Recovery pattern of parameters was compared by correlating the individual slopes of each variable. Initially, a rapid short-term effect of anti-VEGF treatment was documented throughout all functional variables. Progressive functional gain over 1 year was observed for distance visual acuity (P = .011), contrast sensitivity (P ≤ .0001), and mean central retinal sensitivity (P ≤ .0001), but not for reading acuity (P = .31) and maximum reading speed (P = .94). Decrease of absolute scotoma area missed statistical significance over time (P = .053) and also fixation stability did not improve (P = .08). However, lesion size influenced the course of absolute scotoma area (P = .0015), while lesion type had no effect on any visual function variable evaluated. The individual slopes of reading acuity and distance visual acuity showed a moderate correlation; however, all other variables showed only a weak or no significant correlation among each other. Visual recovery in anti-VEGF therapy is reflected in a characteristic pattern of functional changes over time, whereas distance visual acuity does not seem to comprehensively reflect overall visual function gain.

Much of late life cognitive decline is not due to common neurodegenerative pathologies.

The pathologic indices of Alzheimer disease, cerebrovascular disease, and Lewy body disease accumulate in the brains of older persons with and without dementia, but the extent to which they account for late life cognitive decline remains unknown. We tested the hypothesis that these pathologic indices account for the majority of late life cognitive decline. A total of 856 deceased participants from 2 longitudinal clinical-pathologic studies, Rush Memory and Aging Project and Religious Orders Study, completed a mean of 7.5 annual evaluations, including 17 cognitive tests. Neuropathologic examinations provided quantitative measures of global Alzheimer pathology, amyloid load, tangle density, macroscopic infarcts, microinfarcts, and neocortical Lewy bodies. Random coefficient models were used to examine the linear relation of pathologic indices with global cognitive decline. In subsequent analyses, random change point models were used to examine the relation of the pathologic indices with the onset of terminal decline and rates of preterminal and terminal decline (ie, nonlinear decline). Cognition declined a mean of about 0.11 U per year (estimate = -0.109, standard error [SE] = 0.004, p < 0.001), with significant individual differences in rates of decline; the variance estimate for the individual slopes was 0.013 (SE = 0.112, p < 0.001). In separate analyses, global Alzheimer pathology, amyloid, tangles, macroscopic infarcts, and neocortical Lewy bodies were associated with faster rates of decline and explained 22%, 6%, 34%, 2%, and 8% of the variation in decline, respectively. When analyzed simultaneously, the pathologic indices accounted for a total of 41% of the variation in decline, and the majority remained unexplained. Furthermore, in random change point models examining the influence of the pathologic indices on the onset of terminal decline and the preterminal and terminal components of the cognitive trajectory, the common pathologic indices accounted for less than a third of the variation in the onset of terminal decline and rates of preterminal and terminal decline. The pathologic indices of the common causes of dementia are important determinants of cognitive decline in old age and account for a large proportion of the variation in late life cognitive decline. Surprisingly, however, much of the variation in cognitive decline remains unexplained, suggesting that other important determinants of cognitive decline remain to be identified. Identification of the mechanisms that contribute to the large unexplained proportion of cognitive decline is urgently needed to prevent late life cognitive decline.

Exome sequencing in a novel familial neuronal intermediate filament inclusion disease with unknown genetic defect

as a useful quantitative phenotype for GWAS and other omics analyses. Methods:We included non-Hispanic White participants from four prospective community-based cohort studies (ROS, MAP, CHAP, EAS) who were non-demented at study entry and have at least two repeatedmeasures of cognition.Within each cohort, individual cognitive tests were combined to form aggregate measures of global cognition and episodic memory. Genotype data from each cohort was quality controlled and imputed using 1000Genomes reference panel. We used linear mixed effects models to characterize individual paths of change in cognition, modeling age, sex and education as fixed effects and intercept and slope as random effects. For initial screen, we extracted individual residual cognitive slope estimates from the models and fit a linear regression model for each single nucleotide polymorphism (SNP), adjusting for population stratification. Results were meta-analyzed across cohorts. SNPs with p< 5x10 -8 were considered genome-wide significant and p < 5x10 -5 were considered suggestive. Results: A total of 3534 subjects were included. The average age at enrollment in each study ranged from 72 to 81, follow-up ranged from 2-18 years and incidence of clinical diagnosis of AD ranged from 19% to 34%. The most significant loci for decline in both global cognition and episodic memory was APOE (p1⁄43.1x10 -34 and p1⁄42.1x10 -24, respectively). Although no other nonAPOE locus reached genome-wide significance, we found highly suggestive results at two other regions. First, for global cognition, near the EDAR gene with the top locus reaching a p1⁄48.9x10 -8 and second, on the RAB3GAP2 genewith the top locus reaching a p1⁄41.3x10 -7. Results were similar for episodic memory. We are currently analyzing data from two other cohort studies for validation. Top hits will be further investigated with full mixed effects models for all SNPs with p < 5x10 -4. Conclusions: Our findings to date suggest that cognitive decline may be a useful phenotype for identifying genomic variation associated with AD or other factors influencing cognitive decline.

Does anxiety sensitivity correlate with startle habituation? An examination in two independent samples

Individuals with anxiety disorders have previously demonstrated abnormal habituation to aversiveness over time. As anxiety sensitivity (AS), or an individuals' propensity to fear of anxiety-related sensations, has been shown to be a risk factor for anxiety disorders (particularly panic disorder), the present study examined whether AS was also associated with abnormal habituation. This association was examined in two independent samples of undergraduates (Ntotal=178). Habituation was operationalised as the reduction in startle response to multiple startle probes presented over 2.5 minutes and three definitions of this reduction were employed. Results indicated that individuals with higher levels of AS evidenced deficits in startle habituation, but the strength of this relationship was somewhat dependent on the definition of startle habituation, with the most robust definition being an analysis of participants' individual slopes across all nine blinks. The present findings suggest that startle habituation is a key mechanism underlying AS, and may help elucidate the role this risk factor plays in the pathogenesis of anxiety disorders.