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)

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

Risk associated with malaria infection in Tihama Qahtan, Aseer region, Kingdom of Saudi Arabia: 2006-2007

Introduction: Since 2004, the Kingdom of Saudi Arabia has pursued a policy of malaria elimination. The distribution of malaria at this time was constrained to regions located in the South Western part of the country. The present study aimed to understand the risk of malaria infection and factors associated with these events between March 2006 and August 2007 in one part of Aseer region. Methods: The study was carried out in Tihama Qahtan area in the far southeastern part of Aseer, historically the most malaria endemic area of this region. The area covers 54 villages served by three primary health care centres (Wadi Alhayah, Alfarsha and Albuqaa). Malaria cases were detected using passive case detection (PCD) at the three health centres for 18 months from March 2006, each positive case was investigated using patient and household level enquiries. In addition, four cross-sectional surveys in 12 villages were undertaken using rapid diagnostic tests within the catchments of each health centre coinciding with malaria transmission seasons. Results: Among 1840 individuals examined in the PCD survey, 49 (2.7%) were positive for malaria, most were Plasmodium falciparum cases and one was a P. vivax case. The majority of these infections were likely to have been acquired outside of the area and represent imported cases, including those from the neighboring region of Jazan. Among the 18 locally acquired cases, the majority were adult males who slept outdoors. 3623 individuals were screened during the cross-sectional surveys, 16 (0.44%) were positive and infections only detected during peak, potential transmission periods. Conclusion: There was evidence of local malaria transmission in the Tihama Qahtan area in 2006-2007, however prevalence and incidence of new infections was very low, making the future ambitions of elimination biologically feasible. The constant source of imported infections must be considered in the area’s elimination ambitions, alongside strong behavioural community messages about sleeping outdoors unprotected and travel to malaria endemic areas outside the region

A novel missense mutation in ISCA2 causes aberrant splicing and leads to multiple mitochondrial dysfunctions syndrome 4

Copyright \ua9 2024 Al-Hassnan, AlDosary, AlHargan, AlQudairy, Almass, Alahmadi, AlShahrani, AlBakheet, Almuhaizea, Taylor, Colak and Kaya.Background: Iron–sulfur cluster assembly 2 (ISCA2) deficiency is linked to an autosomal recessive disorder known as multiple mitochondrial dysfunctions syndrome 4 (MMDS4). This disorder is characterized by leukodystrophy and neuroregression. Currently, most of the reported patients are from Saudi Arabia. All these patients carry a homozygous founder variant (NM_194279.2:c.229G>A:p.Gly77Ser) in ISCA2. Methods: We describe a patient who underwent full clinical evaluation, including metabolic, neurological, and radiological examinations. Standard genetic testing, including whole exome sequencing coupled with autozygome analysis, was undertaken, as were assessments of mitochondrial DNA (mtDNA) copy number and mtDNA sequencing on DNA extracted from blood and cultured fibroblasts. Functional workup consisted of splicing assessment of ISCA2 using RT-PCR, biochemical assessment of complex I status using dipstick assays, and mitochondrial respiration measurements using a Seahorse XFp analyzer. Results: We present the clinical and functional characterization of a novel homozygous ISCA2 missense variant (NM_194279.3:c.70A>G:p.Arg24Gly), leading to aberrant splicing in a patient presenting with neuroregression, generalized spasticity with exaggerated deep tendon reflexes and head lag, and progressive loss of acquired milestones. The novel variant was fully segregated in a wider family and was absent in a large control cohort, ethnically matching in-house exomes, local databases such as CGMdb and Saudi Human Genome Program, and ClinVar. Conclusions: Our analyses revealed that the variant is pathogenic, disrupting normal ISCA2 splicing and presumably leading to a truncated protein that disturbs metabolic pathways in patient-derived cells

Temporal dynamics in the association between depression and dementia: an umbrella review and meta-analysis

\ua9 2025 The Authors. Background: Identifying modifiable risk factors is crucial for dementia prevention, a global health concern. Depression is considered a risk factor for dementia, but the temporal dynamics across the life course remain inconclusive. Therefore, we aimed to systematically assess the relationship between the timing of depression assessment and risk of all-cause late-life dementia. Methods: We conducted an umbrella review and meta-analysis to assess incident dementia in individuals with non-current history of depression. PubMed and Ovid Embase, MEDLINE, and PsycInfo were searched from inception up to February 17, 2025. Systematic reviews with meta-analyses investigating the association between depression and incident late-life dementia were included. From eligible reviews, we also extracted data from studies reporting dementia risk as hazard ratios (HRs), analysing the timing of depression measurement using random-effects models for meta-analysis. This study is registered with PROSPERO, CRD42021249706. Findings: Of the 7763 records identified, nine reviews were eligible for inclusion of the umbrella review. One review was judged to be of moderate quality, while the others were either low (n = 3) or critically low (n = 5). For our meta-analyses, 18 studies reporting depression onset in later life (n = 901,762 participants, n = 7595 incident dementia cases) and seven studies on depression assessed during midlife (n ≥ 2,501,269 participants, n ≥ 276,929 incident dementia cases) were included. All studies in the meta-analyses were deemed to be of good quality, with no strong evidence of publication bias. Pooled HRs indicated depression present in late-life (HR 1.95, 95% CI: 1.68–2.26; I2 = 77.5%) and midlife (HR 1.56, 95% CI: 1.12–2.18; I2 = 97.5%) significantly increased risk of all-cause dementia. Interpretation: The findings suggest that depression across the life course may increase dementia risk; however, substantial heterogeneity and review quality should be considered when interpreting the strength of this evidence. A life course approach to the treatment and prevention of depression may help reduce the burden of dementia, but this will require scaling up access to effective mental health care for vulnerable populations. Further research is needed to clarify if the stronger late-life association reflects depression as an immediate risk factor or an early manifestation of neurodegenerative processes. Funding: National Institute for Health and Care Research, UK Research and Innovation, and Saudi Arabian Cultural Mission

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

A Study of the Effect of Treatment on the Clinical Profile, Pain, and Disability in Migraine Patients Seen in a Tertiary Hospital [Response to Letter]

Geetha Kandasamy,1 Dalia Almaghaslah,1 Mona Almanasef,1 Tahani Musleh Almeleebia,1 Khalid Orayj,1 Ayesha Siddiqua,1 Eman Shorog,1 Asma M Alshahrani,1 Kousalya Prabahar,2 Vinoth Prabhu Veeramani,2 Palanisamy Amirthalingam,2 Saleh Alqifari,2 Naif Alshahrani,3 Aram Hamad AlSaedi,4 Alhanouf A Alsaab,5 Fatimah Aljohani,6 M Yasmin Begum,7 Akhtar Atiya8 1Department of Clinical Pharmacy, College of Pharmacy, King Khalid University, Abha, Kingdom of Saudi Arabia; 2Department of Pharmacy Practice, Faculty of Pharmacy, University of Tabuk, Tabuk, Kingdom of Saudi Arabia; 3Department of Pharmacy, Ad Diriyah Hospital, Ministry of Health (MOH), Riyadh, 13717, Kingdom of Saudi Arabia; 4College of Medicine, Taibah University, Al Madinah Al Munawwarah, Saudi Arabia; 5Pharmacist at Abha International Private Hospital, Abha, Saudi Arabia; 6Pharmacist at Prince Sultan Armed Forces Hospital, Almadenah Almonwarah, Saudi Arabia; 7Department of Pharmaceutics, College of Pharmacy, King Khalid University, Abha, Kingdom of Saudi Arabia; 8Department of Pharmacognosy, College of Pharmacy, King Khalid University, Abha, Kingdom of Saudi ArabiaCorrespondence: Geetha Kandasamy, Department of Clinical Pharmacy, College of Pharmacy, King Khalid University, Abha, Kingdom of Saudi Arabia, Email [email protected]

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

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

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