Genome-wide association study of prostate cancer-specific survival

BACKGROUND: Unnecessary intervention and overtreatment of indolent disease are common challenges in clinical management of prostate cancer. Improved tools to distinguish lethal from indolent disease are critical. METHODS: We performed a genome-wide survival analysis of cause-specific death in 24,023 prostate cancer patients (3,513 disease-specific deaths) from the PRACTICAL and BPC3 consortia. Top findings were assessed for replication in a Norwegian cohort (CONOR). RESULTS: We observed no significant association between genetic variants and prostate cancer survival. CONCLUSIONS: Common genetic variants with large impact on prostate cancer survival were not observed in this study. IMPACT: Future studies should be designed for identification of rare variants with large effect sizes or common variants with small effect sizes.

A cloud-based intelligent computing system for contextual exploration on personal sleep-tracking data using association rule mining

With the development of wearable and mobile computing technology, more and more people start using sleep-tracking tools to collect personal sleep data on a daily basis aiming at understanding and improving their sleep. While sleep quality is influenced by many factors in a person’s lifestyle context, such as exercise, diet and steps walked, existing tools simply visualize sleep data per se on a dashboard rather than analyse those data in combination with contextual factors. Hence many people find it difficult to make sense of their sleep data. In this paper, we present a cloud-based intelligent computing system named SleepExplorer that incorporates sleep domain knowledge and association rule mining for automated analysis on personal sleep data in light of contextual factors. Experiments show that the same contextual factors can play a distinct role in sleep of different people, and SleepExplorer could help users discover factors that are most relevant to their personal sleep.

A kinetic analysis of the tumor-associated galactopyranosyl-(1→3)-2-acetamido-2-deoxy-α-d-galactopyranoside antigen—lectin interaction

A kinetic study of the tumor-associated galactopyranosyl-(1→3)-2-acetamido-2-deoxy-α-d-galactopyranoside (T-antigen) with lectin peanut agglutinin is described. The disaccharide antigen was synthesized by chemical methods and was functionalized suitably for immobilization onto a carboxy-methylated sensor chip. The ligand immobilized surface was allowed interaction with the lectin peanut agglutinin, which acted as the analyte and the interaction was studied by the surface plasmon resonance method. The ligand—lectin interaction was characterized by the kinetic on-off rates and a bivalent analyte binding model was found to describe the observed kinetic constants. It was identified that the antigen-lectin interaction had a faster association rate constant (k a1) and a slower dissociation rate constant (k d1) in the initial binding step. The subsequent binding step showed much reduced kinetic rates. The antigen-lectin interaction was compared with the kinetic rates of the interaction of a galactopyranosyl-(1→4)-β-d-galactopyranoside derivative and a mannopyranoside derivative with the lectin.

Genetic analysis of structural brain connectivity using DICCCOL models of diffusion MRI in 522 twins

Genetic and environmental factors affect white matter connectivity in the normal brain, and they also influence diseases in which brain connectivity is altered. Little is known about genetic influences on brain connectivity, despite wide variations in the brain's neural pathways. Here we applied the 'DICCCOL' framework to analyze structural connectivity, in 261 twin pairs (522 participants, mean age: 21.8 y ± 2.7SD). We encoded connectivity patterns by projecting the white matter (WM) bundles of all 'DICCCOLs' as a tracemap (TM). Next we fitted an A/C/E structural equation model to estimate additive genetic (A), common environmental (C), and unique environmental/error (E) components of the observed variations in brain connectivity. We found 44 'heritable DICCCOLs' whose connectivity was genetically influenced (α2>1%); half of them showed significant heritability (α2>20%). Our analysis of genetic influences on WM structural connectivity suggests high heritability for some WM projection patterns, yielding new targets for genome-wide association studies.

The association between student characteristics and the development of clinical reasoning in a graduate-entry, PBL medical programme

This study sought to assess the extent to which the entry characteristics of students in a graduate-entry medical programme predict the subsequent development of clinical reasoning ability. Subjects comprised 290 students voluntarily recruited from three successive cohorts of the University of Queensland's MBBS Programme. Clinical reasoning was measured once a year over a period of three years using two methods, a set of 10 Clinical Reasoning Problems (CRPs) and the Diagnostic Thinking Inventory (DTI). Data on gender, age at entry into the programme, nature of primary degree, scores on selection criteria (written examination plus interview) and academic performance in the first two years of the programme were recorded for each student, and their association with clinical reasoning skill analysed using univariate and multivariate analysis. Univariate analysis indicated significant associations between CRP score, gender and primary degree with a significant but small association between DTI and interview score. Stage of progression through the programme was also an important predictor of performance on both indicators. Subsequent multivariate analysis suggested that female gender is a positive predictor of CRP score independently of the nature of a subject's primary degree and stage of progression through the programme, although these latter two variables are interdependent. Positive predictors of clinical reasoning skill are stage of progression through the MBBS programme, female gender and interview score. Although the nature of a student's primary degree is important in the early years of the programme, evidence suggests that by graduation differences between students' clinical reasoning skill due to this factor have been resolved.

Mutational analysis of the insulin‑like growth factor 1 receptor tyrosine kinase domain in non-small cell lung cancer patients

The insulin‑like growth factor 1 receptor (IGF1R) pathway plays an important role in the pathogenesis of non‑small cell lung cancer (NSCLC) and also provides a mechanism of resistance to targeted therapies. IGF1R is therefore an ideal therapeutic target and several inhibitors have entered clinical trials. However, thus far the response to these inhibitors has been poor, highlighting the importance of predictive biomarkers to identify patient cohorts who will benefit from these targeted agents. It is well‑documented that mutations and/or deletions in the epidermal growth factor receptor (EGFR) tyrosine kinase (TK) domain predict sensitivity of NSCLC patients to EGFR TK inhibitors. Single‑nucleotide polymorphisms (SNPs) in the IGF pathway have been associated with disease, including breast and prostate cancer. The aim of the present study was to elucidate whether the IGF1R TK domain harbours SNPs, somatic mutations or deletions in NSCLC patients and correlates the mutation status to patient clinicopathological data and prognosis. Initially 100 NSCLC patients were screened for mutations/deletions in the IGF1R TK domain (exons 16‑21) by sequencing analysis. Following the identification of SNP rs2229765, a further 98 NSCLC patients and 866 healthy disease‑free control patients were genotyped using an SNP assay. The synonymous SNP (rs2229765) was the only aberrant base change identified in the IGF1R TK domain of 100 NSCLC patients initially analysed. SNP rs2229765 was detected in exon 16 and was found to have no significant association between IGF1R expression and survival. The GA genotype was identified in 53.5 and 49.4% of NSCLC patients and control individuals, respectively. No significant difference was found in the genotype (P=0.5487) or allele (P=0.9082) frequencies between the case and control group. The present findings indicate that in contrast to the EGFR TK domain, the IGF1R TK domain is not frequently mutated in NSCLC patients. The synonymous SNP (rs2229765) had no significant association between IGF1R expression and survival in the cohort of NSCLC patients.

Predicting crashes using traffic offences. A meta-analysis that examines potential bias between self-report and archival data

Background Traffic offences have been considered an important predictor of crash involvement, and have often been used as a proxy safety variable for crashes. However the association between crashes and offences has never been meta-analysed and the population effect size never established. Research is yet to determine the extent to which this relationship may be spuriously inflated through systematic measurement error, with obvious implications for researchers endeavouring to accurately identify salient factors predictive of crashes. Methodology and Principal Findings Studies yielding a correlation between crashes and traffic offences were collated and a meta-analysis of 144 effects drawn from 99 road safety studies conducted. Potential impact of factors such as age, time period, crash and offence rates, crash severity and data type, sourced from either self-report surveys or archival records, were considered and discussed. After weighting for sample size, an average correlation of r = .18 was observed over the mean time period of 3.2 years. Evidence emerged suggesting the strength of this correlation is decreasing over time. Stronger correlations between crashes and offences were generally found in studies involving younger drivers. Consistent with common method variance effects, a within country analysis found stronger effect sizes in self-reported data even controlling for crash mean. Significance The effectiveness of traffic offences as a proxy for crashes may be limited. Inclusion of elements such as independently validated crash and offence histories or accurate measures of exposure to the road would facilitate a better understanding of the factors that influence crash involvement.

Evidence for an association with type 2 diabetes mellitus at the PPARG locus in a South Indian population

Peroxisome proliferator activated receptor-gamma 2 (PPARG2) is a nuclear hormone receptor of ligand-dependent ranscription factor involved in adipogenesis and a molecular target of the insulin sensitizers thiazolidinediones. We addressed the question of whether the 3 variants (-1279G/A, Pro12Ala, and His478His) in the PPARG2 gene are associated with type 2 diabetes mellitus and its related traits in a South Indian population. The study subjects (1000 type 2 diabetes mellitus and 1000 normal glucose-tolerant subjects) were chosen randomly from the Chennai Urban Rural Epidemiology Study, an ongoing population-based study in southern India. The variants were screened by single-stranded conformational variant, direct sequencing, and restriction fragment length polymorphism. Linkage disequilibrium was estimated from the estimates of haplotypic frequencies. The -1279G/A, Pro12Ala, and His478His variants of the PPARG2 gene were not associated with type 2 diabetes mellitus. However, the 2-loci analyses showed that, in the presence of Pro/Pro genotype of the Pro12Ala variant, the -1279G/A promoter variant showed increased susceptibility to type 2 diabetes mellitus (odds ratio, 2.092; 95% confidence interval, 1.22-3.59; P = .008), whereas in the presence of 12Ala allele, the -1279G/A showed a protective effect against type 2 diabetes mellitus (odds ratio, 0.270; 95% confidence interval, 0.15-0.49; P < .0001). The 3-loci haplotype analysis showed that the A-Ala-T (-1279G/A-Pro12Ala-His478His) haplotype was associated with a reduced risk of type 2 diabetes mellitus (P < .0001). Although our data indicate that the PPARG2 gene variants, independently, have no association with type 2 diabetes mellitus, the 2-loci genotype analysis involving -1279G/A and Pro12Ala variants and the 3-loci haplotype analysis have shown a significant association with type 2 diabetes mellitus in this South Indian population. (C) 2010 Elsevier Inc. All rights reserved.

Appendiceal sonography in children: A retrospective analysis as a platform for potential implementation of diagnostic categories

- Background Sonography is an important diagnostic tool in children with suspected appendicitis. Reported accuracy and appendiceal visualisation rates vary significantly, as does the management of equivocal ultrasound findings. The aim of this study was to audit appendiceal sonography at a tertiary children's hospital, and provide baseline data for a future prospective study. - Summary of work Records of children who underwent ultrasound studies for possible appendicitis between January 2008 and December 2010 were reviewed. Variables included patient demographics, sonographic appendix characteristics, and secondary signs. Descriptive statistics and analysis using ANOVA, Mann-Whitney U test, and ROC curves were performed. Mater Human Research Ethic Committee approval was granted. - Summary of results There were 457 eligible children. Using a dichotomous diagnostic model (including equivocal results), sensitivity was 89.6%, specificity 91.6%, and diagnostic yield of 40.7%. ROC curve analysis of a 6mm diameter cut-off was 0.88 AUC (95% CI 0.80 to 0.95). - Discussion and conclusions Sonography is an accurate test for acute appendicitis in children, with a high sensitivity and negative predictive value. A diameter of 6mm as an absolute cut-off in a binary model can lead to false findings. Results were compared with available literature. Recent publications propose categorising diameter1 and integrating secondary signs2 to improve accuracy and provide more meaningful results to clinicians. This study will be a benchmark for future studies with multiple diagnostic categorisation.

Mechanism of lectin-cell interactions: thermodynamic and kinetic analysis of the binding of winged bean acidic lectin (WBA II) to human erythrocytes

In order to identify the forces involved in the binding and to understand the mechanism involved, equilibrium and kinetic studies were performed on the binding of the winged bean acidic lectin to human erythrocytes. The magnitudes of delta S and delta H were positive and negative respectively, an observation differing markedly from the lectin-simple sugar interactions where delta S and delta H are generally negative. Analysis of the sign and magnitudes of these values indicate that ionic and hydrogen bonded interactions prevail over hydrophobic interactions resulting in net -ve delta H (-37.12 kJ.mol-1) and +ve delta S (14.4 J.mole-1 K-1 at 20 degrees C), thereby suggesting that this entropy driven reaction also reflects conformational changes in the lectin and/or the receptor. Presence of two kinds of receptors for WBA II on erythrocytes, as observed by equilibrium studies, is consistent with the biexponential dissociation rate constants (at 20 degrees C K1 = 1.67 x 10(-3) M-1 sec-1 and K2 = 11.1 x 10(-3) M-1 sec-1). These two rate constants differed by an order of magnitude accounting for the difference in the association constants of the two receptors of WBA II. However, the association process remains monoexponential suggesting no observable difference in the association rates of the lectin molecule with both the receptors, under the experimental conditions studied. The thermodynamic parameters calculated from kinetic data correlate well with those observed by equilibrium. A two-step binding mechanism is proposed based on the kinetic parameters for WBA II-receptor interaction

Analysis of dynamics and mechanism of ligand binding to Artocarpus integrifolia agglutinin. A 13C and 19F NMR study

Binding of 13C-labeled N-acetylgalactosamine (13C-GalNAc) and N-trifluoroacetylgalactosamine (19F-GalNAc) to Artocarpus integrifolia agglutinin has been studied using 13C and 19F nuclear magnetic resonance spectroscopy, respectively. Binding of these saccharides resulted in broadening of the resonances, and no change in chemical shift was observed, suggesting that the alpha- and beta-anomers of 13C-GalNAc and 19F-GalNAc experience a magnetically equivalent environment in the lectin combining site. The alpha- and beta-anomers of 13C-GalNAc and 19F-GalNAc were found to be in slow exchange between free and protein bound states. Binding of 13C-GalNAc was studied as a function of temperature. From the temperature dependence of the line broadening, the thermodynamic and kinetic parameters were evaluated. The association rate constants obtained for the alpha-anomers of 13C-GalNAc and 19F-GalNAc (k+1 = 1.01 x 10(5) M-1.s-1 and 0.698 x 10(5) M-1.s-1, respectively) are in close agreement with those obtained for the corresponding beta-anomers (k+1 = 0.95 x 10(5) M-1.s-1 and 0.65 x 10(5) M-1.s-1, respectively), suggesting that the two anomers bind to the lectin by a similar mechanism. In addition these values are several orders of magnitude slower than those obtained for diffusion controlled processes. The dissociation rate constants obtained are 49.9, 56.9, 42, and 43 s-1, respectively, for the alpha- and beta-anomers of 13C-GalNAc and 19F-GalNAc. A two-step mechanism has been proposed for the interaction of 13C-GalNAc and 19F-GalNAc with A. integrifolia lectin in view of the slow association rates and high activation entropies. The thermodynamic parameters obtained for the association and dissociation reactions suggest that the binding process is entropically favored and that there is a small enthalpic contribution.

Search for the Higgs Boson Produced in Association with Z→ℓ+ℓ- in pp̅ Collisions at √s=1.96 TeV

We present a search for the Higgs boson in the process $q\bar{q} \to ZH \to \ell^+\ell^- b\bar{b}$. The analysis uses an integrated luminosity of 1 fb$^{-1}$ of $p\bar{p}$ collisions produced at $\sqrt{s} =$ 1.96 TeV and accumulated by the upgraded Collider Detector at Fermilab (CDF II). We employ artificial neural networks both to correct jets mismeasured in the calorimeter, and to distinguish the signal kinematic distributions from those of the background. We see no evidence for Higgs boson production, and set 95% CL upper limits on $\sigma_{ZH} \cdot {\cal B}(H \to b\bar{b}$), ranging from 1.5 pb to 1.2 pb for a Higgs boson mass ($m_H$) of 110 to 150 GeV/$c^2$.

Analysis of gradually and spatially varied flow in sand-bed channels

Seepage through a sand bed affects the channel hydrodynamics, which in turn alters channel stability. Thus, the effect of seepage on its hydrodynamic parameters needs to be ascertained. The present work analyses spatially varied flow of a sand-bed channel subjected to seepage in the downward direction through a sand bed. Numerically calculated flow profiles affected by seepage have been verified using experimental observations. The present work also analyses the friction slope, velocity and bed shear stress variations along the channel for both seepage and no-seepage conditions. It was found that the downward seepage-induced channel flow has larger friction slope and bed shear stress than that of no-seepage.

Improved Search for a Higgs Boson Produced in Association with Z→l+l- in pp̅ Collisions at √s=1.96 TeV

We present a search for the standard model Higgs boson produced with a Z boson in 4.1 fb^-1 of data collected with the CDF II detector at the Tevatron. In events consistent with the decay of the Higgs boson to a bottom-quark pair and the Z boson to electrons or muons, we set 95% credibility level upper limits on the ZH production cross section times the H -> b bbar branching ratio. Improved analysis methods enhance signal sensitivity by 20% relative to previous searches beyond the gain due to the larger data sample. At a Higgs boson mass of 115 GeV/c^2 we set a limit of 5.9 times the standard model value.