Reaching the End-Game for GWAS: Machine Learning Approaches for the Prioritization of Complex Disease Loci.

Genome-wide association studies (GWAS) have revealed thousands of genetic loci that underpin the complex biology of many human traits. However, the strength of GWAS - the ability to detect genetic association by linkage disequilibrium (LD) - is also its limitation. Whilst the ever-increasing study size and improved design have augmented the power of GWAS to detect effects, differentiation of causal variants or genes from other highly correlated genes associated by LD remains the real challenge. This has severely hindered the biological insights and clinical translation of GWAS findings. Although thousands of disease susceptibility loci have been reported, causal genes at these loci remain elusive. Machine learning (ML) techniques offer an opportunity to dissect the heterogeneity of variant and gene signals in the post-GWAS analysis phase. ML models for GWAS prioritization vary greatly in their complexity, ranging from relatively simple logistic regression approaches to more complex ensemble models such as random forests and gradient boosting, as well as deep learning models, i.e., neural networks. Paired with functional validation, these methods show important promise for clinical translation, providing a strong evidence-based approach to direct post-GWAS research. However, as ML approaches continue to evolve to meet the challenge of causal gene identification, a critical assessment of the underlying methodologies and their applicability to the GWAS prioritization problem is needed. This review investigates the landscape of ML applications in three parts: selected models, input features, and output model performance, with a focus on prioritizations of complex disease associated loci. Overall, we explore the contributions ML has made towards reaching the GWAS end-game with consequent wide-ranging translational impact

Photo-induced enhanced Raman spectroscopy (PIERS): Sensing atomic-defects, explosives and biomolecules

Enhanced Raman relies heavily on finding ideal hot-spot regions which enable significant enhancement factors. In addition, the termed “chemical enhancement” aspect of SERS is often neglected due to its relatively low enhancement factors, in comparison to those of electromagnetic (EM) nature. Using a metal-semiconductor hybrid system, with the addition of induced surface oxygen vacancy defects, both EM and chemical enhancement pathways can be utilized on cheap reusable surfaces. Two metal-oxide semiconductor thin films, WO3 and TiO2, were used as a platform for investigating size dependent effects of Au nanoparticles (NPs) for SERS (surface enhanced Raman spectroscopy) and PIERS (photo-induced enhanced Raman spectroscopy – UV pre-irradiation for additional chemical enhancement) detection applications. A set concentration of spherical Au NPs (5, 50, 100 and 150 nm in diameter) was drop-cast on preirradiated metal-oxide substrates. Using 4-mercaptobenzoic acid (MBA) as a Raman reporter molecule, a significant dependence on the size of nanoparticle was found. The greatest surface coverage and ideal distribution of AuNPs was found for the 50 nm particles during SERS tests, resulting in a high probability of finding an ideal hot-spot region. However, more significantly a strong dependence on nanoparticle size was also found for PIERS measurements – completely independent of AuNP distribution and orientation affects – where 50 nm particles were also found to generate the largest PIERS enhancement. The position of the analyte molecule with respect to the metal-semiconductor interface and position of generated oxygen vacancies within the hot-spot regions was presented as an explanation for this result

Relationship of EMAST and Microsatellite Instability Among Patients with Rectal Cancer

Elevated microsatellite instability at selected tetranucleotide repeats (EMAST) is a genetic signature identified in 60% of sporadic colon cancers and may be linked with heterogeneous expression of the DNA mismatch repair (MMR) protein hMSH3. Unlike microsatellite instability-high (MSI-H) in which hypermethylation of hMLH1 occurs followed by multiple susceptible gene mutations, EMAST may be associated with inflammation and subsequent relaxation of MMR function with the biological consequences not known. We evaluated the prevalence of EMAST and MSI in a population-based cohort of rectal cancers, as EMAST has not been previously determined in rectal cancers. We analyzed 147 sporadic cases of rectal cancer using five tetranucleotide microsatellite markers and National-Cancer-Institute-recommended MSI (mononucleotide and dinucleotide) markers. EMAST and MSI determinations were made on analysis of DNA sequences of the polymerase chain reaction products and determined positive if at least two loci were found to have frame-shifted repeats upon comparison between normal and cancer samples from the same patient. We correlated EMAST data with race, gender, and tumor stage and examined the samples for lymphocyte infiltration. Among this cohort of patients with rectal cancer (mean age 62.2 ± 10.3 years, 36% female, 24% African American), 3/147 (2%) showed MSI (three males, two African American) and 49/147 (33%) demonstrated EMAST. Rectal tumors from African Americans were more likely to show EMAST than Caucasians (18/37, 49% vs. 27/104, 26%, p = 0.014) and were associated with advanced stage (18/29, 62% EMAST vs. 18/53, 37%, non-EMAST p = 0.02). There was no association between EMAST and gender. EMAST was more prevalent in rectal tumors that showed peri-tumoral infiltration compared to those without (30/49, 60% EMAST vs. 24/98, 25% non-EMAST, p = 0.0001). EMAST in rectal cancer is common and MSI is rare. EMAST is associated with African-American race and may be more commonly seen with metastatic disease. The etiology and consequences of EMAST are under investigation, but its association with immune cell infiltration suggests that inflammation may play a role for its development

Framing Social Justice: The Ties That Bind a Multinational Occupational Community

The notion of a frame is central to the conceptualisation of social justice and the grounding of social justice claims. Influential theories of social justice are typically grounded in national or cosmopolitan framings. Those entitled to raise claims of injustice are identified as citizens of states or the globe, respectively. The re-visioning of understandings of space and belonging, incumbent in the processes of globalisation, problematises static geographical framings. We offer an alternative lens and argue for the inclusion of sociological data in accounts of social justice to identify the relevant framing of the community of entitlement. Drawing on secondary analysis of a qualitative dataset, we explore the case of multinational seafarers caught at the intersection of competing appeals to nationality and commonality as an exemplar of transnational workers. And, argue that there are compelling grounds to treat this group of multinational seafarers as a community of entitlement

Measurement of the Forward-Backward Asymmetry in the B -> K(*) mu+ mu- Decay and First Observation of the Bs -> phi mu+ mu- Decay

We reconstruct the rare decays $B^+ \to K^+\mu^+\mu^-$, $B^0 \to K^{*}(892)^0\mu^+\mu^-$, and $B^0_s \to \phi(1020)\mu^+\mu^-$ in a data sample corresponding to $4.4 {\rm fb^{-1}}$ collected in $p\bar{p}$ collisions at $\sqrt{s}=1.96 {\rm TeV}$ by the CDF II detector at the Fermilab Tevatron Collider. Using $121 \pm 16$ $B^+ \to K^+\mu^+\mu^-$ and $101 \pm 12$ $B^0 \to K^{*0}\mu^+\mu^-$ decays we report the branching ratios. In addition, we report the measurement of the differential branching ratio and the muon forward-backward asymmetry in the $B^+$ and $B^0$ decay modes, and the $K^{*0}$ longitudinal polarization in the $B^0$ decay mode with respect to the squared dimuon mass. These are consistent with the theoretical prediction from the standard model, and most recent determinations from other experiments and of comparable accuracy. We also report the first observation of the $B^0_s \to \phi\mu^+\mu^- decay and measure its branching ratio${\mathcal{B}}(B^0_s \to \phi\mu^+\mu^-) = [1.44 \pm 0.33 \pm 0.46] \times 10^{-6}$using$27 \pm 6$signal events. This is currently the most rare$B^0_s$ decay observed.Comment: 7 pages, 2 figures, 3 tables. Submitted to Phys. Rev. Let

Performance of CMS muon reconstruction in pp collision events at sqrt(s) = 7 TeV

The performance of muon reconstruction, identification, and triggering in CMS has been studied using 40 inverse picobarns of data collected in pp collisions at sqrt(s) = 7 TeV at the LHC in 2010. A few benchmark sets of selection criteria covering a wide range of physics analysis needs have been examined. For all considered selections, the efficiency to reconstruct and identify a muon with a transverse momentum pT larger than a few GeV is above 95% over the whole region of pseudorapidity covered by the CMS muon system, abs(eta) < 2.4, while the probability to misidentify a hadron as a muon is well below 1%. The efficiency to trigger on single muons with pT above a few GeV is higher than 90% over the full eta range, and typically substantially better. The overall momentum scale is measured to a precision of 0.2% with muons from Z decays. The transverse momentum resolution varies from 1% to 6% depending on pseudorapidity for muons with pT below 100 GeV and, using cosmic rays, it is shown to be better than 10% in the central region up to pT = 1 TeV. Observed distributions of all quantities are well reproduced by the Monte Carlo simulation.Comment: Replaced with published version. Added journal reference and DO

Measurement of the inclusive and dijet cross-sections of b-jets in pp collisions at sqrt(s) = 7 TeV with the ATLAS detector

The inclusive and dijet production cross-sections have been measured for jets containing b-hadrons (b-jets) in proton-proton collisions at a centre-of-mass energy of sqrt(s) = 7 TeV, using the ATLAS detector at the LHC. The measurements use data corresponding to an integrated luminosity of 34 pb^-1. The b-jets are identified using either a lifetime-based method, where secondary decay vertices of b-hadrons in jets are reconstructed using information from the tracking detectors, or a muon-based method where the presence of a muon is used to identify semileptonic decays of b-hadrons inside jets. The inclusive b-jet cross-section is measured as a function of transverse momentum in the range 20 < pT < 400 GeV and rapidity in the range |y| < 2.1. The bbbar-dijet cross-section is measured as a function of the dijet invariant mass in the range 110 < m_jj < 760 GeV, the azimuthal angle difference between the two jets and the angular variable chi in two dijet mass regions. The results are compared with next-to-leading-order QCD predictions. Good agreement is observed between the measured cross-sections and the predictions obtained using POWHEG + Pythia. MC@NLO + Herwig shows good agreement with the measured bbbar-dijet cross-section. However, it does not reproduce the measured inclusive cross-section well, particularly for central b-jets with large transverse momenta.Comment: 10 pages plus author list (21 pages total), 8 figures, 1 table, final version published in European Physical Journal