A novel approach to simulate gene-environment interactions in complex diseases

Background: Complex diseases are multifactorial traits caused by both genetic and environmental factors. They represent the major part of human diseases and include those with largest prevalence and mortality (cancer, heart disease, obesity, etc.). Despite a large amount of information that has been collected about both genetic and environmental risk factors, there are few examples of studies on their interactions in epidemiological literature. One reason can be the incomplete knowledge of the power of statistical methods designed to search for risk factors and their interactions in these data sets. An improvement in this direction would lead to a better understanding and description of gene-environment interactions. To this aim, a possible strategy is to challenge the different statistical methods against data sets where the underlying phenomenon is completely known and fully controllable, for example simulated ones. Results: We present a mathematical approach that models gene-environment interactions. By this method it is possible to generate simulated populations having gene-environment interactions of any form, involving any number of genetic and environmental factors and also allowing non-linear interactions as epistasis. In particular, we implemented a simple version of this model in a Gene-Environment iNteraction Simulator (GENS), a tool designed to simulate case-control data sets where a one gene-one environment interaction influences the disease risk. The main aim has been to allow the input of population characteristics by using standard epidemiological measures and to implement constraints to make the simulator behaviour biologically meaningful. Conclusions: By the multi-logistic model implemented in GENS it is possible to simulate case-control samples of complex disease where gene-environment interactions influence the disease risk. The user has full control of the main characteristics of the simulated population and a Monte Carlo process allows random variability. A knowledge-based approach reduces the complexity of the mathematical model by using reasonable biological constraints and makes the simulation more understandable in biological terms. Simulated data sets can be used for the assessment of novel statistical methods or for the evaluation of the statistical power when designing a study

Radiographic manifestations of experimental aluminum toxicity in growing bone

To evaluate the effect of aluminum on growing bone in the presence of normal renal function, the following experiment was performed. Eight littermate pair-fed pigs (5 weeks old) were randomly assigned to one of two study groups: control C, n =4, or aluminum treated Al, n =4. Daily intravenous injections of either aluminum 1.5 mg/kg/day (Al group) or vehicle only (C group) were given during the 8-week duration of the study. The radiographic findings which appeared in the aluminum-treated group and not in the controls consisted of areas of sclerosis in the submetaphyseal regions and the periphery of epiphyses. In addition there was separation of the anterior tibial tubercle. The growth plates did not increase in width despite the presence of osteomalacia and histologic evidence of extensive deposition of aluminum in bone. The area of sclerosis visualized in the radiographs correlated histologically with thickened bony trabeculae. The increased width of these trabeculae is attributable to an increase in primary spongiosum and broadened seams of osteoid.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/46782/1/256_2004_Article_BF00356955.pd

Cognitive function in a randomized trial of evolocumab

Inga Stuķēna as well as a complete list of investigators is provided in the Supplementary Appendix, available at NEJM.org. https://www.nejm.org/doi/suppl/10.1056/NEJMoa1701131/suppl_file/nejmoa1701131_appendix.pdf Funding Information: (Funded by Amgen; EBBINGHAUS ClinicalTrials.gov number, NCT02207634.) Supported by Amgen. We thank Sarah T. Farias, Ph.D., at UC Davis Health for providing the English-language and translated versions of the Everyday Cognition (ECog) tool. Publisher Copyright: Copyright © 2017 Massachusetts Medical Society.BACKGROUND: Findings from clinical trials of proprotein convertase subtilisin–kexin type 9 (PCSK9) inhibitors have led to concern that these drugs or the low levels of low-density lipoprotein (LDL) cholesterol that result from their use are associated with cognitive deficits. METHODS: In a subgroup of patients from a randomized, placebo-controlled trial of evolocumab added to statin therapy, we prospectively assessed cognitive function using the Cambridge Neuropsychological Test Automated Battery. The primary end point was the score on the spatial working memory strategy index of executive function (scores range from 4 to 28, with lower scores indicating a more efficient use of strategy and planning). Secondary end points were the scores for working memory (scores range from 0 to 279, with lower scores indicating fewer errors), episodic memory (scores range from 0 to 70, with lower scores indicating fewer errors), and psychomotor speed (scores range from 100 to 5100 msec, with faster times representing better performance). Assessments of cognitive function were performed at baseline, week 24, yearly, and at the end of the trial. The primary analysis was a noninferiority comparison of the mean change from baseline in the score on the spatial working memory strategy index of executive function between the patients who received evolocumab and those who received placebo; the noninferiority margin was set at 20% of the standard deviation of the score in the placebo group. RESULTS: A total of 1204 patients were followed for a median of 19 months; the mean (±SD) change from baseline over time in the raw score for the spatial working memory strategy index of executive function (primary end point) was −0.21±2.62 in the evolocumab group and −0.29±2.81 in the placebo group (P<0.001 for noninferiority; P=0.85 for superiority). There were no significant between-group differences in the secondary end points of scores for working memory (change in raw score, −0.52 in the evolocumab group and −0.93 in the placebo group), episodic memory (change in raw score, −1.53 and −1.53, respectively), or psychomotor speed (change in raw score, 5.2 msec and 0.9 msec, respectively). In an exploratory analysis, there were no associations between LDL cholesterol levels and cognitive changes. CONCLUSIONS: In a randomized trial involving patients who received either evolocumab or placebo in addition to statin therapy, no significant between-group difference in cognitive function was observed over a median of 19 months.publishersversionPeer reviewe

Genetic linkage analysis in the age of whole-genome sequencing

For many years, linkage analysis was the primary tool used for the genetic mapping of Mendelian and complex traits with familial aggregation. Linkage analysis was largely supplanted by the wide adoption of genome-wide association studies (GWASs). However, with the recent increased use of whole-genome sequencing (WGS), linkage analysis is again emerging as an important and powerful analysis method for the identification of genes involved in disease aetiology, often in conjunction with WGS filtering approaches. Here, we review the principles of linkage analysis and provide practical guidelines for carrying out linkage studies using WGS data

Expression of Drug Targets in Patients Treated with Sorafenib, Carboplatin and Paclitaxel

Introduction: Sorafenib, a multitarget kinase inhibitor, targets members of the mitogen-activated protein kinase (MAPK) pathway and VEGFR kinases. Here we assessed the association between expression of sorafenib targets and biomarkers of taxane sensitivity and response to therapy in pre-treatment tumors from patients enrolled in ECOG 2603, a phase III comparing sorafenib, carboplatin and paclitaxel (SCP) to carboplatin, paclitaxel and placebo (CP). Methods: Using a method of automated quantitative analysis (AQUA) of in situ protein expression, we quantified expression of VEGF-R2, VEGF-R1, VEGF-R3, FGF-R1, PDGF-Rβ, c-Kit, B-Raf, C-Raf, MEK1, ERK1/2, STMN1, MAP2, EB1 and Bcl-2 in pretreatment specimens from 263 patients. Results: An association was found between high FGF-R1 and VEGF-R1 and increased progression-free survival (PFS) and overall survival (OS) in our combined cohort (SCP and CP arms). Expression of FGF-R1 and VEGF-R1 was higher in patients who responded to therapy ((CR+PR) vs. (SD+PD+ un-evaluable)). Conclusions: In light of the absence of treatment effect associated with sorafenib, the association found between FGF-R1 and VEGF-R1 expression and OS, PFS and response might reflect a predictive biomarker signature for carboplatin/paclitaxel-based therapy. Seeing that carboplatin and pacitaxel are now widely used for this disease, corroboration in another cohort might enable us to improve the therapeutic ratio of this regimen. © 2013 Jilaveanu et al

Sustainability of treatment effect of a 3-year early intervention programme for first-episode psychosis

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Hepatic Abnormalities Associated with Aluminum Loading in Piglets

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/141476/1/jpen0293.pd

Cosmogenic neutron production at the Sudbury Neutrino Observatory

Neutrons produced in nuclear interactions initiated by cosmic-ray muons present an irreducible background to many rare-event searches, even in detectors located deep underground. Models for the production of these neutrons have been tested against previous experimental data, but the extrapolation to deeper sites is not well understood. Here we report results from an analysis of cosmogenically produced neutrons at the Sudbury Neutrino Observatory. A specific set of observables are presented, which can be used to benchmark the validity of geant4 physics models. In addition, the cosmogenic neutron yield, in units of 10-4 cm2/(g·μ), is measured to be 7.28±0.09(stat)-1.12+1.59(syst) in pure heavy water and 7.30±0.07(stat)-1.02+1.40(syst) in NaCl-loaded heavy water. These results provide unique insights into this potential background source for experiments at SNOLAB

High "Normal" blood glucose is associated with decreased brain volume and cognitive performance in the 60s: the PATH through Life Study

Context:Type 2 diabetes is associated with cerebral atrophy, cognitive impairment and dementia. We recently showed higher glucose levels in the normal range not to be free of adverse effects and to be associated with greater hippocampal and amygdalar atrophy in older community-dwelling individuals free of diabetes.Objective:This study aimed to determine whether blood glucose levels in the normal range

SUP: an extension to SLINK to allow a larger number of marker loci to be simulated in pedigrees conditional on trait values

BACKGROUND: With the recent advances in high-throughput genotyping technologies that allow for large-scale association mapping of human complex traits, promising statistical designs and methods have been emerging. Efficient simulation software are key elements for the evaluation of the properties of new statistical tests. SLINK is a flexible simulation tool that has been widely used to generate the segregation and recombination processes of markers linked to, and possibly associated with, a trait locus, conditional on trait values in arbitrary pedigrees. In practice, its most serious limitation is the small number of loci that can be simulated, since the complexity of the algorithm scales exponentially with this number. RESULTS: I describe the implementation of a two-step algorithm to be used in conjunction with SLINK to enable the simulation of a large number of marker loci linked to a trait locus and conditional on trait values in families, with the possibility for the loci to be in linkage disequilibrium. SLINK is used in the first step to simulate genotypes at the trait locus conditional on the observed trait values, and also to generate an indicator of the descent path of the simulated alleles. In the second step, marker alleles or haplotypes are generated in the founders, conditional on the trait locus genotypes simulated in the first step. Then the recombination process between the marker loci takes place conditionally on the descent path and on the trait locus genotypes. This two-step implementation is often computationally faster than other software that are designed to generate marker data linked to, and possibly associated with, a trait locus. CONCLUSION: Because the proposed method uses SLINK to simulate the segregation process, it benefits from its flexibility: the trait may be qualitative with the possibility of defining different liability classes (which allows for the simulation of gene-environment interactions or even the simulation of multi-locus effects between unlinked susceptibility regions) or it may be quantitative and normally distributed. In particular, this implementation is the only one available that can generate a large number of marker loci conditional on the set of observed quantitative trait values in pedigrees