Quantile-Specific Penetrance of Genes Affecting Lipoproteins, Adiposity and Height

Quantile-dependent penetrance is proposed to occur when the phenotypic expression of a SNP depends upon the population percentile of the phenotype. To illustrate the phenomenon, quantiles of height, body mass index (BMI), and plasma lipids and lipoproteins were compared to genetic risk scores (GRS) derived from single nucleotide polymorphisms (SNP)s having established genome-wide significance: 180 SNPs for height, 32 for BMI, 37 for low-density lipoprotein (LDL)-cholesterol, 47 for high-density lipoprotein (HDL)-cholesterol, 52 for total cholesterol, and 31 for triglycerides in 1930 subjects. Both phenotypes and GRSs were adjusted for sex, age, study, and smoking status. Quantile regression showed that the slope of the genotype-phenotype relationships increased with the percentile of BMI (P = 0.002), LDL-cholesterol (P = 3×10−8), HDL-cholesterol (P = 5×10−6), total cholesterol (P = 2.5×10−6), and triglyceride distribution (P = 7.5×10−6), but not height (P = 0.09). Compared to a GRS's phenotypic effect at the 10th population percentile, its effect at the 90th percentile was 4.2-fold greater for BMI, 4.9-fold greater for LDL-cholesterol, 1.9-fold greater for HDL-cholesterol, 3.1-fold greater for total cholesterol, and 3.3-fold greater for triglycerides. Moreover, the effect of the rs1558902 (FTO) risk allele was 6.7-fold greater at the 90th than the 10th percentile of the BMI distribution, and that of the rs3764261 (CETP) risk allele was 2.4-fold greater at the 90th than the 10th percentile of the HDL-cholesterol distribution. Conceptually, it maybe useful to distinguish environmental effects on the phenotype that in turn alters a gene's phenotypic expression (quantile-dependent penetrance) from environmental effects affecting the gene's phenotypic expression directly (gene-environment interaction)

Hundreds of variants clustered in genomic loci and biological pathways affect human height

Most common human traits and diseases have a polygenic pattern of inheritance: DNA sequence variants at many genetic loci influence the phenotype. Genome-wide association (GWA) studies have identified more than 600 variants associated with human traits, but these typically explain small fractions of phenotypic variation, raising questions about the use of further studies. Here, using 183,727 individuals, we show that hundreds of genetic variants, in at least 180 loci, influence adult height, a highly heritable and classic polygenic trait. The large number of loci reveals patterns with important implications for genetic studies of common human diseases and traits. First, the 180 loci are not random, but instead are enriched for genes that are connected in biological pathways (P = 0.016) and that underlie skeletal growth defects (P < 0.001). Second, the likely causal gene is often located near the most strongly associated variant: in 13 of 21 loci containing a known skeletal growth gene, that gene was closest to the associated variant. Third, at least 19 loci have multiple independently associated variants, suggesting that allelic heterogeneity is a frequent feature of polygenic traits, that comprehensive explorations of already-discovered loci should discover additional variants and that an appreciable fraction of associated loci may have been identified. Fourth, associated variants are enriched for likely functional effects on genes, being over-represented among variants that alter amino-acid structure of proteins and expression levels of nearby genes. Our data explain approximately 10% of the phenotypic variation in height, and we estimate that unidentified common variants of similar effect sizes would increase this figure to approximately 16% of phenotypic variation (approximately 20% of heritable variation). Although additional approaches are needed to dissect the genetic architecture of polygenic human traits fully, our findings indicate that GWA studies can identify large numbers of loci that implicate biologically relevant genes and pathways.

Detecting Subtle Changes in Visuospatial Executive Function and Learning in the Amnestic Variant of Mild Cognitive Impairment

BACKGROUND AND PURPOSE: Amnestic mild cognitive impairment (aMCI) is a putative prodromal stage of Alzheimer's disease (AD) characterized by deficits in episodic verbal memory. Our goal in the present study was to determine whether executive dysfunction may also be detectable in individuals diagnosed with aMCI. METHODS: This study used a hidden maze learning test to characterize component processes of visuospatial executive function and learning in a sample of 62 individuals with aMCI compared with 94 healthy controls. RESULTS: Relative to controls, individuals with aMCI made more exploratory/learning errors (Cohen's d = .41). Comparison of learning curves revealed that the slope between the first two of five learning trials was four times as steep for controls than for individuals with aMCI (Cohen's d = .64). Individuals with aMCI also made a significantly greater number of rule-break/error monitoring errors across learning trials (Cohen's d = .21). CONCLUSIONS: These results suggest that performance on a task of complex visuospatial executive function is compromised in individuals with aMCI, and likely explained by reductions in initial strategy formulation during early visual learning and "on-line" maintenance of task rules

Improved general regression network for protein domain boundary prediction

Background: Protein domains present some of the most useful information that can be used to understand protein structure and functions. Recent research on protein domain boundary prediction has been mainly based on widely known machine learning techniques, such as Artificial Neural Networks and Support Vector Machines. In this study, we propose a new machine learning model (IGRN) that can achieve accurate and reliable classification, with significantly reduced computations. The IGRN was trained using a PSSM (Position Specific Scoring Matrix), secondary structure, solvent accessibility information and inter-domain linker index to detect possible domain boundaries for a target sequence. Results: The proposed model achieved average prediction accuracy of 67% on the Benchmark_2 dataset for domain boundary identification in multi-domains proteins and showed superior predictive performance and generalisation ability among the most widely used neural network models. With the CASP7 benchmark dataset, it also demonstrated comparable performance to existing domain boundary predictors such as DOMpro, DomPred, DomSSEA, DomCut and DomainDiscovery with 70.10% prediction accuracy. Conclusion: The performance of proposed model has been compared favourably to the performance of other existing machine learning based methods as well as widely known domain boundary predictors on two benchmark datasets and excels in the identification of domain boundaries in terms of model bias, generalisation and computational requirements. © 2008 Yoo et al; licensee BioMed Central Ltd

A VLP-based vaccine targeting domain III of the West Nile virus E protein protects from lethal infection in mice

Background. Since its first appearance in the USA in 1999, West Nile virus (WNV) has spread in the Western hemisphere and continues to represent an important public health concern. In the absence of effective treatment, there is a medical need for the development of a safe and efficient vaccine. Live attenuated WNV vaccines have shown promise in preclinical and clinical studies but might carry inherent risks due to the possibility of reversion to more virulent forms. Subunit vaccines based on the large envelope (E) glycoprotein of WNV have therefore been explored as an alternative approach. Although these vaccines were shown to protect from disease in animal models, multiple injections and/or strong adjuvants were required to reach efficacy, underscoring the need for more immunogenic, yet safe DIII-based vaccines. Results. We produced a conjugate vaccine against WNV consisting of recombinantly expressed domain III (DIII) of the E glycoprotein chemically cross-linked to virus-like particles derived from the recently discovered bacteriophage AP205. In contrast to isolated DIII protein, which required three administrations to induce detectable antibody titers in mice, high titers of DIII-specific antibodies were induced after a single injection of the conjugate vaccine. These antibodies were able to neutralize the virus in vitro and provided partial protection from a challenge with a lethal dose of WNV. Three injections of the vaccine induced high titers of virus-neutralizing antibodies, and completely protected mice from WNV infection. Conclusions. The immunogenicity of DIII can be strongly enhanced by conjugation to virus-like particles of the bacteriophage AP205. The superior immunogenicity of the conjugate vaccine with respect to other DIII-based subunit vaccines, its anticipated favourable safety profile and low production costs highlight its potential as an efficacious and cost-effective prophylaxis against WNV

Sonographic assessment of abdominal fat distribution in infancy

There is growing evidence that not only the total amount of fat, but also the distribution of body fat determines risks for metabolic and cardiovascular disease. Developmental studies on factors influencing body fat distribution have been hampered by a lack of appropriate techniques for measuring intraabdominal fat in early life. Sonography, which is an established method for assessing abdominal fat distribution in adults, has not yet been evaluated in infants. To adapt the sonographic measurement of abdominal fat distribution to infants and study its reliability. The Generation R study, a population-based prospective cohort study. We included 212 one- and 227 two-year old Dutch infants in the present analysis. Sixty-two infants underwent replicate measurements to assess reproducibility. We developed a standardized protocol to measure the thickness of (1) subcutaneous and (2) preperitoneal fat in the upper abdomen of infants. To this end we defined infancy specific measurement areas to quantify fat thickness. Reproducibility of fat measurements was good to excellent with intraclass correlation coefficients of 0.93–0.97 for intra-observer agreement and of 0.89–0.95 for inter-observer agreement. We observed a pronounced increase in preperitoneal fat thickness in the second year of life while subcutaneous fat thickness increased only slightly, resulting in an altered body fat distribution. Gender did not significantly influence fat distribution in the first two years of life. Our age specific protocol for the sonographic measurement of central subcutaneous and preperitoneal fat is a reproducible method that can be instrumental for investigating fat distribution in early life

Performance of the CMS Cathode Strip Chambers with Cosmic Rays

The Cathode Strip Chambers (CSCs) constitute the primary muon tracking device in the CMS endcaps. Their performance has been evaluated using data taken during a cosmic ray run in fall 2008. Measured noise levels are low, with the number of noisy channels well below 1%. Coordinate resolution was measured for all types of chambers, and fall in the range 47 microns to 243 microns. The efficiencies for local charged track triggers, for hit and for segments reconstruction were measured, and are above 99%. The timing resolution per layer is approximately 5 ns

Linear low-dose extrapolation for noncancer health effects is the exception, not the rule

The nature of the exposure-response relationship has a profound influence on risk analyses. Several arguments have been proffered as to why all exposure-response relationships for both cancer and noncarcinogenic end-points should be assumed to be linear at low doses. We focused on three arguments that have been put forth for noncarcinogens. First, the general “additivity-to-background” argument proposes that if an agent enhances an already existing disease-causing process, then even small exposures increase disease incidence in a linear manner. This only holds if it is related to a specific mode of action that has nonuniversal properties—properties that would not be expected for most noncancer effects. Second, the “heterogeneity in the population” argument states that variations in sensitivity among members ofthe target population tend to “flatten out and linearize” the exposure-response curve, but this actually only tends to broaden, not linearize, the dose-response relationship. Third, it has been argued that a review of epidemiological evidence shows linear or no-threshold effects at low exposures in humans, despite nonlinear exposure-response in the experimental dose range in animal testing for similar endpoints. It is more likely that this is attributable to exposure measurement error rather than a true non-threshold association. Assuming that every chemical is toxic at high exposures and linear at low exposures does not comport to modern-day scientific knowledge of biology. There is no compelling evidence-based justification for a general low-exposure linearity; rather, case-specific mechanistic arguments are needed

Family physicians\u27 professional identity formation: a study protocol to explore impression management processes in institutional academic contexts.

BACKGROUND: Despite significant differences in terms of medical training and health care context, the phenomenon of medical students\u27 declining interest in family medicine has been well documented in North America and in many other developed countries as well. As part of a research program on family physicians\u27 professional identity formation initiated in 2007, the purpose of the present investigation is to examine in-depth how family physicians construct their professional image in academic contexts; in other words, this study will allow us to identify and understand the processes whereby family physicians with an academic appointment seek to control the ideas others form about them as a professional group, i.e. impression management. METHODS/DESIGN: The methodology consists of a multiple case study embedded in the perspective of institutional theory. Four international cases from Canada, France, Ireland and Spain will be conducted; the \u22case\u22 is the medical school. Four levels of analysis will be considered: individual family physicians, interpersonal relationships, family physician professional group, and organization (medical school). Individual interviews and focus groups with academic family physicians will constitute the main technique for data generation, which will be complemented with a variety of documentary sources. Discourse techniques, more particularly rhetorical analysis, will be used to analyze the data gathered. Within- and cross-case analysis will then be performed. DISCUSSION: This empirical study is strongly grounded in theory and will contribute to the scant body of literature on family physicians\u27 professional identity formation processes in medical schools. Findings will potentially have important implications for the practice of family medicine, medical education and health and educational policies

Comparing the Functional Independence Measure and the interRAI/MDS for use in the functional assessment of older adults: a review of the literature

<p>Abstract</p> <p>Background</p> <p>The rehabilitation of older persons is often complicated by increased frailty and medical complexity - these in turn present challenges for the development of health information systems. Objective investigation and comparison of the effectiveness of geriatric rehabilitation services requires information systems that are comprehensive, reliable, valid, and sensitive to clinically relevant changes in older persons. The Functional Independence Measure is widely used in rehabilitation settings - in Canada this is used as the central component of the National Rehabilitation Reporting System of the Canadian Institute of Health Information. An alternative system has been developed by the interRAI consortium. We conducted a literature review to compare the development and measurement properties of these two systems.</p> <p>Methods</p> <p>English language literature published between 1983 (initial development of the FIM) and 2008 was searched using Medline and CINAHL databases, and the reference lists of retrieved articles. Relevant articles were summarized and charted using the criteria proposed by Streiner. Additionally, attention was paid to the ability of the two systems to address issues particularly relevant to older rehabilitation clients, such as medical complexity, comorbidity, and responsiveness to small but clinically meaningful improvements.</p> <p>Results</p> <p>In total, 66 articles were found that met the inclusion criteria. The majority of FIM articles studied inpatient rehabilitation settings; while the majority of interRAI/MDS articles focused on nursing home settings. There is evidence supporting the reliability of both instruments. There were few articles that investigated the construct validity of the interRAI/MDS.</p> <p>Conclusion</p> <p><b>A</b>dditional psychometric research is needed on both the FIM and MDS, especially with regard to their use in different settings and with different client groups.</p