Functional annotation signatures of disease susceptibility loci improve SNP association analysis.

BACKGROUND: Genetic association studies are conducted to discover genetic loci that contribute to an inherited trait, identify the variants behind these associations and ascertain their functional role in determining the phenotype. To date, functional annotations of the genetic variants have rarely played more than an indirect role in assessing evidence for association. Here, we demonstrate how these data can be systematically integrated into an association study's analysis plan. RESULTS: We developed a Bayesian statistical model for the prior probability of phenotype-genotype association that incorporates data from past association studies and publicly available functional annotation data regarding the susceptibility variants under study. The model takes the form of a binary regression of association status on a set of annotation variables whose coefficients were estimated through an analysis of associated SNPs in the GWAS Catalog (GC). The functional predictors examined included measures that have been demonstrated to correlate with the association status of SNPs in the GC and some whose utility in this regard is speculative: summaries of the UCSC Human Genome Browser ENCODE super-track data, dbSNP function class, sequence conservation summaries, proximity to genomic variants in the Database of Genomic Variants and known regulatory elements in the Open Regulatory Annotation database, PolyPhen-2 probabilities and RegulomeDB categories. Because we expected that only a fraction of the annotations would contribute to predicting association, we employed a penalized likelihood method to reduce the impact of non-informative predictors and evaluated the model's ability to predict GC SNPs not used to construct the model. We show that the functional data alone are predictive of a SNP's presence in the GC. Further, using data from a genome-wide study of ovarian cancer, we demonstrate that their use as prior data when testing for association is practical at the genome-wide scale and improves power to detect associations. CONCLUSIONS: We show how diverse functional annotations can be efficiently combined to create 'functional signatures' that predict the a priori odds of a variant's association to a trait and how these signatures can be integrated into a standard genome-wide-scale association analysis, resulting in improved power to detect truly associated variants

Supply sensitive services in Swiss ambulatory care: An analysis of basic health insurance records for 2003-2007

<p>Abstract</p> <p>Background</p> <p>Swiss ambulatory care is characterized by independent, and primarily practice-based, physicians, receiving fee for service reimbursement. This study analyses supply sensitive services using ambulatory care claims data from mandatory health insurance. A first research question was aimed at the hypothesis that physicians with large patient lists decrease their intensity of services and bill less per patient to health insurance, and vice versa: physicians with smaller patient lists compensate for the lack of patients with additional visits and services. A second research question relates to the fact that several cantons are allowing physicians to directly dispense drugs to patients ('self-dispensation') whereas other cantons restrict such direct sales to emergencies only. This second question was based on the assumption that patterns of rescheduling patients for consultations may differ across channels of dispensing prescription drugs and therefore the hypothesis of different consultation costs in this context was investigated.</p> <p>Methods</p> <p>Complete claims data paid for by mandatory health insurance of all Swiss physicians in own practices were analyzed for the years 2003-2007. Medical specialties were pooled into six main provider types in ambulatory care: primary care, pediatrics, gynecology & obstetrics, psychiatrists, invasive and non-invasive specialists. For each provider type, regression models at the physician level were used to analyze the relationship between the number of patients treated and the total sum of treatment cost reimbursed by mandatory health insurance.</p> <p>Results</p> <p>The results show non-proportional relationships between patient numbers and total sum of treatment cost for all provider types involved implying that treatment costs per patient increase with higher practice size. The related additional costs to the health system are substantial. Regions with self-dispensation had lowest treatment cost for primary care, gynecology, pediatrics and for psychiatrists whereas "prescription only" areas had lowest cost for specialists with non-invasive and invasive activities.</p> <p>Conclusions</p> <p>The results indicate that payment methods for services and for prescription drugs are associated with variations in treatment cost that are unlikely warranted by different medical needs of patients alone. Promoting physician accountability of care by linking reimbursements to quality, not quantity, of services are important policy measures to be considered for health care in Switzerland.</p

Functional Integration of Grafted Neural Stem Cell-Derived Dopaminergic Neurons Monitored by Optogenetics in an In Vitro Parkinson Model

Intrastriatal grafts of stem cell-derived dopamine (DA) neurons induce behavioral recovery in animal models of Parkinson's disease (PD), but how they functionally integrate in host neural circuitries is poorly understood. Here, Wnt5a-overexpressing neural stem cells derived from embryonic ventral mesencephalon of tyrosine hydroxylase-GFP transgenic mice were expanded as neurospheres and transplanted into organotypic cultures of wild type mouse striatum. Differentiated GFP-labeled DA neurons in the grafts exhibited mature neuronal properties, including spontaneous firing of action potentials, presence of post-synaptic currents, and functional expression of DA D2 autoreceptors. These properties resembled those recorded from identical cells in acute slices of intrastriatal grafts in the 6-hydroxy-DA-induced mouse PD model and from DA neurons in intact substantia nigra. Optogenetic activation or inhibition of grafted cells and host neurons using channelrhodopsin-2 (ChR2) and halorhodopsin (NpHR), respectively, revealed complex, bi-directional synaptic interactions between grafted cells and host neurons and extensive synaptic connectivity within the graft. Our data demonstrate for the first time using optogenetics that ectopically grafted stem cell-derived DA neurons become functionally integrated in the DA-denervated striatum. Further optogenetic dissection of the synaptic wiring between grafted and host neurons will be crucial to clarify the cellular and synaptic mechanisms underlying behavioral recovery as well as adverse effects following stem cell-based DA cell replacement strategies in PD

Leisure time physical activity in middle age predicts the metabolic syndrome in old age: results of a 28-year follow-up of men in the Oslo study

<p>Abstract</p> <p>Background</p> <p>Data are scarce on the long term relationship between leisure time physical activity, smoking and development of metabolic syndrome and diabetes. We wanted to investigate the relationship between leisure time physical activity and smoking measured in middle age and the occurrence of the metabolic syndrome and diabetes in men that participated in two cardiovascular screenings of the Oslo Study 28 years apart.</p> <p>Methods</p> <p>Men residing in Oslo and born in 1923–32 (n = 16 209) were screened for cardiovascular diseases and risk factors in 1972/3. Of the original cohort, those who also lived in same area in 2000 were invited to a repeat screening examination, attended by 6 410 men. The metabolic syndrome was defined according to a modification of the National Cholesterol Education Program criteria. Leisure time physical activity, smoking, educational attendance and the presence of diabetes were self-reported.</p> <p>Results</p> <p>Leisure time physical activity decreased between the first and second screening and tracked only moderately between the two time points (Spearman's ρ = 0.25). Leisure time physical activity adjusted for age and educational attendance was a significant predictor of both the metabolic syndrome and diabetes in 2000 (odds ratio for moderately vigorous versus sedentary/light activity was 0.65 [95% CI, 0.54–0.80] for the metabolic syndrome and 0.68 [0.52–0.91] for diabetes) (test for trend P < 0.05). However, when adjusted for more factors measured in 1972/3 including glucose, triglycerides, body mass index, treated hypertension and systolic blood pressure these associations were markedly attenuated. Smoking was associated with the metabolic syndrome but not with diabetes in 2000.</p> <p>Conclusion</p> <p>Physical activity during leisure recorded in middle age prior to the current waves of obesity and diabetes had an independent predictive association with the presence of the metabolic syndrome but not significantly so with diabetes 28 years later in life, when the subjects were elderly.</p

Geographical variation in radiological services: a nationwide survey

BACKGROUND: Geographical variation in health care services challenges the basic principle of fair allocation of health care resources. This study aimed to investigate geographical variation in the use of X-ray, CT, MRI and Ultrasound examinations in Norway, the contribution from public and private institutions, and the impact of accessibility and socioeconomic factors on variation in examination rates. METHODS: A nationwide survey of activity in all radiological institutions for the year 2002 was used to compare the rates per thousand of examinations in the counties. The data format was files/printouts where the examinations were recorded according to a code system. RESULTS: Overall rates per thousand of radiological examinations varied by a factor of 2.4. The use of MRI varied from 170 to 2, and CT from 216 to 56 examinations per 1000 inhabitants. Single MRI examinations (knee, cervical spine and head/brain) ranged high in variation, as did certain other spine examinations. For examination of specific organs, the counties' use of one modality was positively correlated with the use of other modalities. Private institutions accounted for 28% of all examinations, and tended towards performing a higher proportion of single examinations with high variability. Indicators of accessibility correlated positively to variation in examination rates, partly due to the figures from the county of Oslo. Correlations between examination rates and socioeconomic factors were also highly influenced by the figures from this county. CONCLUSION: The counties use of radiological services varied substantially, especially CT and MRI examinations. A likely cause of the variation is differences in accessibility. The coexistence of public and private institutions may be a source of variability, along with socioeconomic factors. The findings represent a challenge to the objective of equality in access to health care services, and indicate a potential for better allocation of overall health care resources. PREVIOUS PUBLICATION: The data applied in this article was originally published in Norwegian in: Børretzen I, Lysdahl KB, Olerud HM: Radiologi i Noreg – undersøkingsfrekvens per 2002, tidstrendar, geografisk variasjon og befolkningsdose. StrålevernRapport 2006:6. Østerås: The Norwegian Radiation Protection Authority. The Norwegian Radiation Protection Authority has given the authors permission to republish the data

What causes increasing and unnecessary use of radiological investigations? a survey of radiologists' perceptions

<p>Abstract</p> <p>Background</p> <p>Growth in use and overuse of diagnostic imaging significantly impacts the quality and costs of health care services. What are the modifiable factors for increasing and unnecessary use of radiological services? Various factors have been indentified, but little is known about their relative impact. Radiologists hold key positions for providing such knowledge. Therefore the purpose of this study was to obtain radiologists' perspective on the causes of increasing and unnecessary use of radiological investigations.</p> <p>Methods</p> <p>In a mailed questionnaire radiologist members of the Norwegian Medical Association were asked to rate potential causes of increased investigation volume (fifteen items) and unnecessary investigations (six items), using five-point-scales. Responses were analysed by using summary statistics and Factor Analysis. Associations between variables were determined using Students' t-test, Spearman rank correlation and Chi-Square tests.</p> <p>Results</p> <p>The response rate was 70% (374/537). The highest rated causes of increasing use of radiological investigations were: a) new radiological technology, b) peoples' demands, c) clinicians' intolerance for uncertainty, d) expanded clinical indications, and e) availability. 'Over-investigation' and 'insufficient referral information' were reported the most frequent causes of unnecessary investigations. Correlations between causes of increasing and unnecessary radiology use were identified.</p> <p>Conclusion</p> <p>In order to manage the growth in radiological imaging and curtail inappropriate investigations, the study findings point to measures that influence the supply and demand of services, specifically to support the decision-making process of physicians.</p

Amino Acid Similarity Accounts for T Cell Cross-Reactivity and for “Holes” in the T Cell Repertoire

Background: Cytotoxic T cell (CTL) cross-reactivity is believed to play a pivotal role in generating immune responses but the extent and mechanisms of CTL cross-reactivity remain largely unknown. Several studies suggest that CTL clones can recognize highly diverse peptides, some sharing no obvious sequence identity. The emerging realization in the field is that T cell receptors (TcR) recognize multiple distinct ligands. Principal Findings: First, we analyzed peptide scans of the HIV epitope SLFNTVATL (SFL9) and found that TCR specificity is position dependent and that biochemically similar amino acid substitutions do not drastically affect recognition. Inspired by this, we developed a general model of TCR peptide recognition using amino acid similarity matrices and found that such a model was able to predict the cross-reactivity of a diverse set of CTL epitopes. With this model, we were able to demonstrate that seemingly distinct T cell epitopes, i.e., ones with low sequence identity, are in fact more biochemically similar than expected. Additionally, an analysis of HIV immunogenicity data with our model showed that CTLs have the tendency to respond mostly to peptides that do not resemble self-antigens. Conclusions: T cell cross-reactivity can thus, to an extent greater than earlier appreciated, be explained by amino acid similarity. The results presented in this paper will help resolving some of the long-lasting discussions in the field of T cel

A Prospective study of the association between weight changes and self-rated health

<p>Abstract</p> <p>Background</p> <p>Obesity and self-rated health (SRH) are strong predictors of morbidity and mortality but their interrelation is sparsely studied. The aim of this study was to analyse the association between weight changes and changes in SRH among women. We also examined if poor SRH at baseline was associated with later weight gain.</p> <p>Methods</p> <p>The Danish Nurse Cohort Study is a prospective population study (1993–1999) and comprises 13,684 female nurses aged 44 to 69 years. Logistic regression analyses were used to examine the association between weight changes and changes in SRH.</p> <p>Results</p> <p>Women who gained weight during the study period had higher odds of reporting poorer self-rated health (Odds Ratio (OR): 1.18, 95% CI: 1.04–1.35). Weight loss among overweight women, did not result in an increase in self-rated health ratings, in fully adjusted analyses (0.96 (95% CI: 0.76–1.23). Poor self-rated health combined with normal weight at first examination was associated with higher odds of later weight gain (OR: 1.29, 95% CI: 1.10–1.51).</p> <p>Conclusion</p> <p>Weight changes may result in lower SRH. Further, poor self-rated health at baseline seems to predict an increase in weight, among women without any longstanding chronic diseases. Future obesity prevention may focus on normal weight individuals with poor SRH.</p

Anti-cancer activities of allyl isothiocyanate and its conjugated silicon quantum dots

Allyl isothiocyanate (AITC), a dietary phytochemical in some cruciferous vegetables, exhibits promising anticancer activities in many cancer models. However, previous data showed AITC to have a biphasic effect on cell viability, DNA damage and migration in human hepatoma HepG2 cells. Moreover, in a 3D co-culture of HUVEC with pericytes, it inhibited tube formation at high doses but promoted this at low doses, which confirmed its biphasic effect on angiogenesis. siRNA knockdown of Nrf2 and glutathione inhibition abolished the stimulation effect of AITC on cell migration and DNA damage. The biological activity of a novel AITC-conjugated silicon quantum dots (AITC-SiQDs) has been investigated for the first time. AITC-SiQDs showed similar anti-cancer properties to AITC at high doses while avoiding the low doses stimulation effect. In addition, AITC-SiQDs showed a lower and long-lasting activation of Nrf2 translocation into nucleus which correlated with their levels of cellular uptake, as detected by the intrinsic fluorescence of SiQDs. ROS production could be one of the mechanisms behind the anti-cancer effect of AITC-SiQDs. These data provide novel insights into the biphasic effect of AITC and highlight the application of nanotechnology to optimize the therapeutic potential of dietary isothiocyanates in cancer treatment

Protein C Mutation (A267T) Results in ER Retention and Unfolded Protein Response Activation

BACKGROUND: Protein C (PC) deficiency is associated with a high risk of venous thrombosis. Recently, we identified the PC-A267T mutation in a patient with PC deficiency and revealed by in vitro studies decreased intracellular and secreted levels of the mutant. The aim of the present study was to characterize the underlying mechanism(s). METHODOLOGY/PRINCIPAL FINDINGS: CHO-K1 cells stably expressing the wild-type (PC-wt) or the PC mutant were generated. In order to examine whether the PC mutant was subjected to increased intracellular degradation, the cells were treated with several inhibitors of various degradation pathways and pulse-chase experiments were performed. Protein-chaperone complexes were analyzed by treating the cells with a cross-linker followed by Western blotting (WB). Expression levels of the immunoglobulin-binding protein (BiP) and the phosphorylated eukaryotic initiation factor 2α (P-eIF2α), both common ER stress markers, were determined by WB to examine if the mutation induced ER stress and unfolded protein response (UPR) activation. We found no major differences in the intracellular degradation between the PC variants. The PC mutant was retained in the endoplasmic reticulum (ER) and had increased association with the Grp-94 and calreticulin chaperones. Retention of the PC-A267T in ER resulted in UPR activation demonstrated by increased expression levels of the ER stress markers BiP and P-eIF2α and caused also increased apoptotic activity in CHO-K1 cells as evidenced by elevated levels of DNA fragmentation. CONCLUSIONS/SIGNIFICANCE: The reduced intracellular level and impaired secretion of the PC mutant were due to retention in ER. In contrast to other PC mutations, retention of the PC-A267T in ER resulted in minor increased proteasomal degradation, rather it induced ER stress, UPR activation and apoptosis