Statistical Methods for Rare Variant Association

Deoxyribonucleic acid (DNA) sequencing allows researchers to conduct more complete assessments of low-frequency and rare genetic variants. In anticipation of the availability of next-generation sequencing data, there is increasing interest in investigating associations between complex traits and rare variants (RVs). In contrast to association studies of common variants (CVs), due to the low frequencies of RVs, common wisdom suggests that existing statistical tests for CVs might not work, motivating the recent development of several new tests that analyze RVs, most of which are based on the idea of pooling/collapsing RVs. Genome-wide association studies (GWAS) based on common SNPs gained more attention in the last few years and have been regularly used to examine complex genetic compositions of diseases and quantitative traits. GWASs have not discovered everything associated with diseases and genetic variations. However, recent empirical evidence has demonstrated that low-frequency and rare variants are, in fact, connected to complex diseases. This thesis will focus on the study of rare variant association. Aggregation tests, where multiple rare variants are analyzed jointly, have incorporated weighting schemes on variants. However, their power is very much dependent on the weighting scheme. I will address three topics in this thesis: the definition of rare variants and their call file (VCF) and a description of the methods that have been used in rare variant analysis. Finally, I will illustrate challenges involved in the analysis of rare variants and propose different weighting schemes for them. Therefore, since the efficiency of rare variant studies might be considerably improved by the application of an appropriate weighting scheme, choosing the proper weighting scheme is the topic of the thesis. In the following chapters, I will propose different weighting schemes, where weights are applied at the level of the variant, the individual or the cell (i.e. the individual genotype call), as well as a weighting scheme that can incorporate quality measures for variants (i.e., a quality score for variant calls) and cells (i.e., genotype quality)

Optical and structural investigation of a 10 μm InAs/GaSb type-II superlattice on GaAs

We report on a 10 μm InAs/GaSb type-II superlattice (T2SL) grown by molecular beam epitaxy on a GaAs substrate using an interfacial misfit (IMF) array and investigate the optical and structural properties in comparison with a T2SL grown on a GaSb substrate. The reference T2SL on GaSb is of high structural quality as evidenced in the high-resolution x-ray diffraction (HRXRD) measurement. The full width at half maximum (FWHM) of the HRXRD peak of the T2SL on GaAs is 5 times larger than that on GaSb. The long-wave infrared (LWIR) emission spectra were analyzed, and the observed transitions were in good agreement with the calculated emission energies. The photoluminescence (PL) intensity maxima (Imax) of ∼10 μm at 77 K is significantly reduced by a factor of 8.5 on the GaAs substrate. The peak fitting analysis of the PL profile indicates the formation of sub-monolayer features at the interfaces. PL mapping highlights the non-uniformity of the T2SL on GaAs which corroborates with Nomarski imaging, suggesting an increase in defect density

Influence of premolar extraction or non-extraction orthodontic therapy on the angular changes of mandibular third molars

Abstract Aim: To compare the angular changes of the third molars relative to the occlusal planeand to the second molar long axis in extraction group and compare these changes with a non extractiongroup.Materials and methods: The study included pre and post treatment panoramic radiographrecords of 90 subjects treated by first premolar extractions and 90 subjects who had been treatedwith non extraction orthodontic therapy (n=90). Two angular variables were measured. Firstly,the angle between the long axis of the third molar and the occlusal plane (M3–OP) and secondly,the angle between the long axis of the third molar and the long axis of the second molar (M3–M2).Data were analyzed by paired and student’s t-test.Result: The analyzed data to assess the changes in the third molar angulation from pretreatmentto post treatment did not vary significantly in both the groups (pdecreased angular values. The M3–OP angular difference was (7.3± 2.45) in extraction group ascompared to (5.85 ± 1.77) in non extraction group. The M3–M2 angular difference of (4.26±3.11) in extraction group and (2.98 ±1.74) in non-extraction group was observedConclusion: Extraction of premolars did not demonstrate considerable changes on the angulationof the third molars. The factors other than premolar extractions may influence the angulationof the third molars.</p

Identification of Significant \u3cem\u3eE\u3c/em\u3e0 Strength in the 2\u3csub\u3e2\u3c/sub\u3e\u3csup\u3e+\u3c/sup\u3e → 2\u3csub\u3e1\u3c/sub\u3e\u3csup\u3e+\u3c/sup\u3e Transitions of \u3csup\u3e58,60,62\u3c/sup\u3eNi

The E0 transition strength in the 22+ → 21+ transitions of 58,60,62Ni have been determined for the first time following a series of measurements at the Australian National University (ANU) and the University of Kentucky (UK). The CAESAR Compton-suppressed HPGe array and the Super-e solenoid at ANU were used to measure the δ(E2/M1) mixing ratio and internal conversion coefficient of each transition following inelastic proton scattering. Level half-lives, δ(E2/M1) mixing ratios and γ-ray branching ratios were measured at UK following inelastic neutron scattering. The new spectroscopic information was used to determine the E0 strengths. These are the first 2+ → 2+ E0 transition strengths measured in nuclei with spherical ground states and the E0 component is found to be unexpectedly large; in fact, these are amongst the largest E0 transition strengths in medium and heavy nuclei reported to date

Identification of significant E0E0 strength in the 22+→21+2^+_2 \rightarrow 2^+_1 transitions of 58,60,62^{58, 60, 62}Ni

The $E0$ transition strength in the $2^+_2 \rightarrow 2^+_1$ transitions of $^{58,60,62}$Ni have been determined for the first time following a series of measurements at the Australian National University (ANU) and the University of Kentucky (UK). The CAESAR Compton-suppressed HPGe array and the Super-e solenoid at ANU were used to measure the $\delta(E2/M1)$ mixing ratio and internal conversion coefficient of each transition following inelastic proton scattering. Level half-lives, $\delta(E2/M1)$ mixing ratios and $\gamma$-ray branching ratios were measured at UK following inelastic neutron scattering. The new spectroscopic information was used to determine the $E0$ strengths. These are the first $2^+ \rightarrow 2^+$ $E0$ transition strengths measured in nuclei with spherical ground states and the $E0$ component is found to be unexpectedly large; in fact, these are amongst the largest $E0$ transition strengths in medium and heavy nuclei reported to date

A robust computational investigation on C₆₀ fullerene nanostructure as a novel sensor to detect SCNˉ

This study explored on the adsorption properties and electronic structure of SCNˉ via density functional theory analysis on the exterior surfaces of C₆₀ and CNTs using B3LYP functional and 6-31G** standard basis set. Then adsorption of SCNˉ through nitrogen atom on the C60 fullerene is electrostatic (₋48.02 kJ molˉ1) in comparison with the C₅₉Al fullerene that shows covalently attached to fullerene surface (₋389.10 kJ mol̄ˉ1). Our calculations demonstrate that the SCNˉ adsorption on the pristine and Al-doped single-walled CNTs are ₋173.13 and ₋334.43 kJ molˉ1, indicating that the SCNˉ can be chemically bonded on the surface of Al-doped CNTs. Moreover, the adsorption of SCNˉ on the C₆₀ surface is weaker in comparison with C₅₉B, C₅₉Al, and C₅₉Ga systems but its electronic sensitivity improved in comparison with those of C₅₉B, C₅₉Al, and C₅₉Ga fullerenes. The evaluation of adsorption energy, energy gap, and dipole moment demonstrates that the pure fullerene can be exploited in the design practice as an SCNˉ sensor and C₅₉Al can be used for SCNˉ removal application

SPARC 2018 Internationalisation and collaboration : Salford postgraduate annual research conference book of abstracts

Welcome to the Book of Abstracts for the 2018 SPARC conference. This year we not only celebrate the work of our PGRs but also the launch of our Doctoral School, which makes this year’s conference extra special. Once again we have received a tremendous contribution from our postgraduate research community; with over 100 presenters, the conference truly showcases a vibrant PGR community at Salford. These abstracts provide a taster of the research strengths of their works, and provide delegates with a reference point for networking and initiating critical debate. With such wide-ranging topics being showcased, we encourage you to take up this great opportunity to engage with researchers working in different subject areas from your own. To meet global challenges, high impact research inevitably requires interdisciplinary collaboration. This is recognised by all major research funders. Therefore engaging with the work of others and forging collaborations across subject areas is an essential skill for the next generation of researchers

Antimicrobial de-escalation in the critically ill patient and assessment of clinical cure: the DIANA study

Purpose: The DIANA study aimed to evaluate how often antimicrobial de-escalation (ADE) of empirical treatment is performed in the intensive care unit (ICU) and to estimate the effect of ADE on clinical cure on day 7 following treatment initiation. Methods: Adult ICU patients receiving empirical antimicrobial therapy for bacterial infection were studied in a prospective observational study from October 2016 until May 2018. ADE was defined as (1) discontinuation of an antimicrobial in case of empirical combination therapy or (2) replacement of an antimicrobial with the intention to narrow the antimicrobial spectrum, within the first 3&nbsp;days of therapy. Inverse probability (IP) weighting was used to account for time-varying confounding when estimating the effect of ADE on clinical cure. Results: Overall, 1495 patients from 152 ICUs in 28 countries were studied. Combination therapy was prescribed in 50%, and carbapenems were prescribed in 26% of patients. Empirical therapy underwent ADE, no change and change other than ADE within the first 3&nbsp;days in 16%, 63% and 22%, respectively. Unadjusted mortality at day 28 was 15.8% in the ADE cohort and 19.4% in patients with no change [p = 0.27; RR 0.83 (95% CI 0.60\u20131.14)]. The IP-weighted relative risk estimate for clinical cure comparing ADE with no-ADE patients (no change or change other than ADE) was 1.37 (95% CI 1.14\u20131.64). Conclusion: ADE was infrequently applied in critically ill-infected patients. The observational effect estimate on clinical cure suggested no deleterious impact of ADE compared to no-ADE. However, residual confounding is likely

Elective Cancer Surgery in COVID-19-Free Surgical Pathways During the SARS-CoV-2 Pandemic: An International, Multicenter, Comparative Cohort Study.

PURPOSE: As cancer surgery restarts after the first COVID-19 wave, health care providers urgently require data to determine where elective surgery is best performed. This study aimed to determine whether COVID-19-free surgical pathways were associated with lower postoperative pulmonary complication rates compared with hospitals with no defined pathway. PATIENTS AND METHODS: This international, multicenter cohort study included patients who underwent elective surgery for 10 solid cancer types without preoperative suspicion of SARS-CoV-2. Participating hospitals included patients from local emergence of SARS-CoV-2 until April 19, 2020. At the time of surgery, hospitals were defined as having a COVID-19-free surgical pathway (complete segregation of the operating theater, critical care, and inpatient ward areas) or no defined pathway (incomplete or no segregation, areas shared with patients with COVID-19). The primary outcome was 30-day postoperative pulmonary complications (pneumonia, acute respiratory distress syndrome, unexpected ventilation). RESULTS: Of 9,171 patients from 447 hospitals in 55 countries, 2,481 were operated on in COVID-19-free surgical pathways. Patients who underwent surgery within COVID-19-free surgical pathways were younger with fewer comorbidities than those in hospitals with no defined pathway but with similar proportions of major surgery. After adjustment, pulmonary complication rates were lower with COVID-19-free surgical pathways (2.2% v 4.9%; adjusted odds ratio [aOR], 0.62; 95% CI, 0.44 to 0.86). This was consistent in sensitivity analyses for low-risk patients (American Society of Anesthesiologists grade 1/2), propensity score-matched models, and patients with negative SARS-CoV-2 preoperative tests. The postoperative SARS-CoV-2 infection rate was also lower in COVID-19-free surgical pathways (2.1% v 3.6%; aOR, 0.53; 95% CI, 0.36 to 0.76). CONCLUSION: Within available resources, dedicated COVID-19-free surgical pathways should be established to provide safe elective cancer surgery during current and before future SARS-CoV-2 outbreaks