GIGI: An Approach to Effective Imputation of Dense Genotypes on Large Pedigrees

Recent emergence of the common-disease-rare-variant hypothesis has renewed interest in the use of large pedigrees for identifying rare causal variants. Genotyping with modern sequencing platforms is increasingly common in the search for such variants but remains expensive and often is limited to only a few subjects per pedigree. In population-based samples, genotype imputation is widely used so that additional genotyping is not needed. We now introduce an analogous approach that enables computationally efficient imputation in large pedigrees. Our approach samples inheritance vectors (IVs) from a Markov Chain Monte Carlo sampler by conditioning on genotypes from a sparse set of framework markers. Missing genotypes are probabilistically inferred from these IVs along with observed dense genotypes that are available on a subset of subjects. We implemented our approach in the Genotype Imputation Given Inheritance (GIGI) program and evaluated the approach on both simulated and real large pedigrees. With a real pedigree, we also compared imputed results obtained from this approach with those from the population-based imputation program BEAGLE. We demonstrated that our pedigree-based approach imputes many alleles with high accuracy. It is much more accurate for calling rare alleles than is population-based imputation and does not require an outside reference sample. We also evaluated the effect of varying other parameters, including the marker type and density of the framework panel, threshold for calling genotypes, and population allele frequencies. By leveraging information from existing genotypes already assayed on large pedigrees, our approach can facilitate cost-effective use of sequence data in the pursuit of rare causal variants

Trajectory of functional outcome and health status after moderate-to-major trauma in Hong Kong: A prospective 5 year cohort study

Background Trauma care systems in Asia have been developing in recent years, but there has been little long-term outcome data from injured survivors. This study aims to evaluate the trajectory of functional outcome and health status up to five years after moderate to major trauma in Hong Kong. Methods We report the five year follow up results of a multicentre, prospective cohort from the trauma registries of three regional trauma centres in Hong Kong. The original cohort recruited 400 adult trauma patients with ISS ≥ 9. Telephone follow up was conducted longitudinally at seven time points, and the extended Glasgow Outcome Scale (GOSE) and Short-Form 36 (SF36) were tracked. Results 119 out of 309 surviving patients (39%) completed follow up after 5 years. The trajectory of GOSE, PCS and MCS showed gradual improvements over the seven time points. 56/119 (47.1%) patients reported a GOSE = 8 (upper good recovery), and the mean PCS and MCS was 47.8 (95% CI 45.8, 49.9) and 55.8 (95% CI 54.1, 57.5) respectively at five years. Univariate logistic regression showed change in PCS - baseline to 1 year and 1 year to 2 years, and change in MCS - baseline to 1 year were associated with GOSE = 8 at 5 years. Linear mixed effects model showed differences in PCS and MCS were greatest between 1-month and 6-month follow up. Conclusions After injury, the most rapid improvement in PCS and MCS occurred in the first six to 12 months, but further recovery was still evident for MCS in patients aged under 65 years for up to five years

Circulating human leucine-rich a-2-glycoprotein 1 mRNA and protein levels to detect acute appendicitis in patients with acute abdominal pain

Background Elevated levels of circulating plasma and urine leucine-rich-2-glycoprotein-1 (LRG1) protein has been found in patients with acute appendicitis (AA) and may be useful for diagnosis. This study aimed to investigate whether combined tests including circulating LRG1 mRNA levels improve the early diagnosis of AA. Methods Between December 2011 and October 2012, a prospective study was conducted on patients aged 18 years or older presenting to the ED with acute abdominal pain (< 7 days of symptom onset). Levels of whole blood LRG1 mRNA and plasma LRG1 protein taken from these patients within 24 h of arrival (mean 12.4 h) were analyzed. The primary outcome was AA. Results Eighty-four patients (40 (47.6%) with AA and 44 (52.4%) without AA; mean age 35 years; 41.6% males) were recruited. Median whole blood LRG1 mRNA and plasma LRG1 levels were higher in AA patients than in non-AA. Of 40 AA patients, 13 (32.5%) were diagnosed as complicated AA. In ROC analysis of LRG1 mRNA (normalized to GAPDH), LRG1 protein and Alvarado score for discriminating AA and non-AA, the areas under the curve (AUC) were 0.723, 0.742 and 0.805 respectively. The AUC of combination of normalized LRG1 mRNA, LRG1 protein and Alvarado score was 0.845. Conclusion A combination of modified whole blood LRG1 mRNA levels, plasma LRG1 protein and Alvarado score at the ED may be useful to diagnose simple and complicated AA from other causes of abdominal pain

Personal preferences for Personalised Trials among patients with chronic diseases: an empirical Bayesian analysis of a conjoint survey.

OBJECTIVE: To describe individual patient preferences for Personalised Trials and to identify factors and conditions associated with patient preferences. DESIGN: Each participant was presented with 18 conjoint questions via an online survey. Each question provided two choices of Personalised Trials that were defined by up to eight attributes, including treatment types, clinician involvement, study logistics and trial burden on a patient. SETTING: Online survey of adults with at least two common chronic conditions in the USA. PARTICIPANTS: A nationally representative sample of 501 individuals were recruited from the Chronic Illness Panel by Harris Poll Online. Participants were recruited from several sources, including emails, social media and telephone recruitment of the target population. MAIN OUTCOME MEASURES: The choice of Personalised Trial design that the participant preferred with each conjoint question. RESULTS: There was large variability in participants\u27 preferences for the design of Personalised Trials. On average, they preferred certain attributes, such as a short time commitment and no cost. Notably, a population-level analysis correctly predicted 62% of the conjoint responses. An empirical Bayesian analysis of the conjoint data, which supported the estimation of individual-level preferences, improved the accuracy to 86%. Based on estimates of individual-level preferences, patients with chronic pain preferred a long study duration (p≤0.001). Asthma patients were less averse to participation burden in terms of data-collection frequency than patients with other conditions (p=0.002). Patients with hypertension were more cost-sensitive (p\u3c0.001). CONCLUSION: These analyses provide a framework for elucidating individual-level preferences when implementing novel patient-centred interventions. The data showed that patient preference in Personalised Trials is highly variable, suggesting that individual differences must be accounted for when marketing Personalised Trials. These results have implications for advancing precise interventions in Personalised Trials by indicating when rigorous scientific principles, such as frequent monitoring, is feasible in a substantial subset of patients

Matrix Models

Matrix models and their connections to String Theory and noncommutative geometry are discussed. Various types of matrix models are reviewed. Most of interest are IKKT and BFSS models. They are introduced as 0+0 and 1+0 dimensional reduction of Yang--Mills model respectively. They are obtained via the deformations of string/membrane worldsheet/worldvolume. Classical solutions leading to noncommutative gauge models are considered.Comment: Lectures given at the Winter School on Modern Trends in Supersymmetric Mechanics, March 2005 Frascati; 38p

NS5-branes in IIA supergravity and gravitational anomalies

We construct a gravitational-anomaly-free effective action for the coupled system of IIA D=10 dynamical supergravity interacting with an NS5-brane. The NS5-brane is considered as elementary in that the associated current is a delta-function supported on its worldvolume. Our approach is based on a Chern-kernel which encodes the singularities of the three-form field strength near the brane in an SO(4)-invariant way and provides a solution for its Bianchi identity in terms of a two-form potential. A dimensional reduction of the recently constructed anomaly-free effective action for an elementary M5-brane in D=11 is seen to reproduce our ten-dimensional action. The Chern-kernel approach provides in particular a concrete realization of the anomaly cancellation mechanism envisaged by Witten.Comment: LaTex, 31 pages, no figure

Post-lockdown abatement of COVID-19 by fast periodic switching

COVID-19 abatement strategies have risks and uncertainties which could lead to repeating waves of infection. We show—as proof of concept grounded on rigorous mathematical evidence—that periodic, high-frequency alternation of into, and out-of, lockdown effectively mitigates second-wave effects, while allowing continued, albeit reduced, economic activity. Periodicity confers (i) predictability, which is essential for economic sustainability, and (ii) robustness, since lockdown periods are not activated by uncertain measurements over short time scales. In turn—while not eliminating the virus—this fast switching policy is sustainable over time, and it mitigates the infection until a vaccine or treatment becomes available, while alleviating the social costs associated with long lockdowns. Typically, the policy might be in the form of 1-day of work followed by 6-days of lockdown every week (or perhaps 2 days working, 5 days off) and it can be modified at a slow-rate based on measurements filtered over longer time scales. Our results highlight the potential efficacy of high frequency switching interventions in post lockdown mitigation. All code is available on Github at https://github.com/V4p1d/FPSP_Covid19. A software tool has also been developed so that interested parties can explore the proof-of-concept system

Product-Group Unification in Type IIB String Thoery

The product-group unification is a model of unified theories, in which masslessness of the two Higgs doublets and absence of dimension-five proton decay are guaranteed by a symmetry. It is based on SU(5) x U(N) (N=2,3) gauge group. It is known that various features of the model are explained naturally, when it is embedded in a brane world. This article describes an idea of how to accommodate all the particles of the model in Type IIB brane world. The GUT-breaking sector is realized by a D3--D7 system, and chiral quarks and leptons arise from intersection of D7-branes. The D-brane configuration can be a geometric realization of the non-parallel family structure of quarks and leptons, an idea proposed to explain the large mixing angles observed in the neutrino oscillation. The tri-linear interaction of the next-to-minimal supersymmetric standard model is obtained naturally in some cases.Comment: 33 pages, 5 figure

Search for contact interactions, large extra dimensions and finite quark radius in ep collisions at HERA

A search for physics beyond the Standard Model has been performed with high-Q^2 neutral current deep inelastic scattering events recorded with the ZEUS detector at HERA. Two data sets, e^+ p \to e^+ X and e^- p \to e^- X, with respective integrated luminosities of 112 pb^-1 and 16 pb^-1, were analyzed. The data reach Q^2 values as high as 40000 GeV^2. No significant deviations from Standard Model predictions were observed. Limits were derived on the effective mass scale in eeqq contact interactions, the ratio of leptoquark mass to the Yukawa coupling for heavy leptoquark models and the mass scale parameter in models with large extra dimensions. The limit on the quark charge radius, in the classical form factor approximation, is 0.85 10^-16 cm.Comment: 28 pages, 4 figures, accepted for publication in Physics Letters

Search for a W' boson decaying to a bottom quark and a top quark in pp collisions at sqrt(s) = 7 TeV

Results are presented from a search for a W' boson using a dataset corresponding to 5.0 inverse femtobarns of integrated luminosity collected during 2011 by the CMS experiment at the LHC in pp collisions at sqrt(s)=7 TeV. The W' boson is modeled as a heavy W boson, but different scenarios for the couplings to fermions are considered, involving both left-handed and right-handed chiral projections of the fermions, as well as an arbitrary mixture of the two. The search is performed in the decay channel W' to t b, leading to a final state signature with a single lepton (e, mu), missing transverse energy, and jets, at least one of which is tagged as a b-jet. A W' boson that couples to fermions with the same coupling constant as the W, but to the right-handed rather than left-handed chiral projections, is excluded for masses below 1.85 TeV at the 95% confidence level. For the first time using LHC data, constraints on the W' gauge coupling for a set of left- and right-handed coupling combinations have been placed. These results represent a significant improvement over previously published limits.Comment: Submitted to Physics Letters B. Replaced with version publishe