Many existing cohorts contain a range of relatedness between genotyped individuals, either by design or by chance. Haplotype estimation in such cohorts is a central step in many downstream analyses. ...Using genotypes from six cohorts from isolated populations and two cohorts from non-isolated populations, we have investigated the performance of different phasing methods designed for nominally 'unrelated' individuals. We find that SHAPEIT2 produces much lower switch error rates in all cohorts compared to other methods, including those designed specifically for isolated populations. In particular, when large amounts of IBD sharing is present, SHAPEIT2 infers close to perfect haplotypes. Based on these results we have developed a general strategy for phasing cohorts with any level of implicit or explicit relatedness between individuals. First SHAPEIT2 is run ignoring all explicit family information. We then apply a novel HMM method (duoHMM) to combine the SHAPEIT2 haplotypes with any family information to infer the inheritance pattern of each meiosis at all sites across each chromosome. This allows the correction of switch errors, detection of recombination events and genotyping errors. We show that the method detects numbers of recombination events that align very well with expectations based on genetic maps, and that it infers far fewer spurious recombination events than Merlin. The method can also detect genotyping errors and infer recombination events in otherwise uninformative families, such as trios and duos. The detected recombination events can be used in association scans for recombination phenotypes. The method provides a simple and unified approach to haplotype estimation, that will be of interest to researchers in the fields of human, animal and plant genetics.
The human genome is characterised by many runs of homozygous genotypes, where identical haplotypes were inherited from each parent. The length of each run is determined partly by the number of ...generations since the common ancestor: offspring of cousin marriages have long runs of homozygosity (ROH), while the numerous shorter tracts relate to shared ancestry tens and hundreds of generations ago. Human populations have experienced a wide range of demographic histories and hold diverse cultural attitudes to consanguinity. In a global population dataset, genome-wide analysis of long and shorter ROH allows categorisation of the mainly indigenous populations sampled here into four major groups in which the majority of the population are inferred to have: (a) recent parental relatedness (south and west Asians); (b) shared parental ancestry arising hundreds to thousands of years ago through long term isolation and restricted effective population size (N(e)), but little recent inbreeding (Oceanians); (c) both ancient and recent parental relatedness (Native Americans); and (d) only the background level of shared ancestry relating to continental N(e) (predominantly urban Europeans and East Asians; lowest of all in sub-Saharan African agriculturalists), and the occasional cryptically inbred individual. Moreover, individuals can be positioned along axes representing this demographic historic space. Long runs of homozygosity are therefore a globally widespread and under-appreciated characteristic of our genomes, which record past consanguinity and population isolation and provide a distinctive record of the demographic history of an individual's ancestors. Individual ROH measures will also allow quantification of the disease risk arising from polygenic recessive effects.
Runs of Homozygosity in European Populations McQuillan, Ruth; Leutenegger, Anne-Louise; Abdel-Rahman, Rehab ...
American journal of human genetics
83, Številka:
3
Journal Article
Recenzirano
Odprti dostop
Estimating individual genome-wide autozygosity is important both in the identification of recessive disease variants via homozygosity mapping and in the investigation of the effects of genome-wide ...homozygosity on traits of biomedical importance. Approaches have tended to involve either single-point estimates or rather complex multipoint methods of inferring individual autozygosity, all on the basis of limited marker data. Now, with the availability of high-density genome scans, a multipoint, observational method of estimating individual autozygosity is possible. Using data from a 300,000 SNP panel in 2618 individuals from two isolated and two more-cosmopolitan populations of European origin, we explore the potential of estimating individual autozygosity from data on runs of homozygosity (ROHs). Termed F
roh, this is defined as the proportion of the autosomal genome in runs of homozygosity above a specified length. Mean F
roh distinguishes clearly between subpopulations classified in terms of grandparental endogamy and population size. With the use of good pedigree data for one of the populations (Orkney), F
roh was found to correlate strongly with the inbreeding coefficient estimated from pedigrees (r = 0.86). Using pedigrees to identify individuals with no shared maternal and paternal ancestors in five, and probably at least ten, generations, we show that ROHs measuring up to 4 Mb are common in demonstrably outbred individuals. Given the stochastic variation in ROH number, length, and location and the fact that ROHs are important whether ancient or recent in origin, approaches such as this will provide a more useful description of genomic autozygosity than has hitherto been possible.
Background Urogenital schistosomiasis and HIV/AIDS infections are widespread in sub-Saharan Africa (SSA) leading to substantial morbidity and mortality. The co-occurrence of both diseases has led to ...the possible hypothesis that urogenital schistosomiasis leads to increased risk of acquiring HIV infection. However, the available evidence concerning this association is inconsistent. The aim of this study was to systematically review and quantitatively synthesize studies that investigated the association between urogenital schistosomiasis and HIV/AIDS infection. Methods A systematic review basing on PRISMA guidelines was conducted. It is registered with PROSPERO, number CRD42018116648. We searched four databases, MEDLINE, EMBASE, Global Health and Global Index Medicus for studies investigating the association between urogenital schistosomiasis and HIV infection. Only studies published in English were considered. Results of the association were summarised by gender. A meta-analysis was performed for studies on females using random-effects model and a pooled OR with 95% confidence interval was reported. Results Of the 993 studies screened, only eight observational studies met the inclusion criteria. Across all studies, the reported unadjusted OR ranged from 0.78 to 3.76. The pooled estimate of unadjusted OR among females was 1.31 (95% CI: 0.87-1.99). Only four of the eight studies reported an adjusted OR. A separate meta-analysis done in the three studies among females that reported an adjusted OR showed that the pooled estimate was 1.85 (95% CI: 1.17-2.92). There were insufficient data to pool results for association between urogenital schistosomiasis and HIV infection in the males. Conclusion Our investigation supports the hypothesis of an association between urogenital schistosomiasis with HIV/AIDS infection in females. Due to insufficient evidence, no conclusion could be drawn in males with urogenital schistosomiasis. Large-scale prospective studies are needed in future.
Introduction
Despite the growing evidence on patient and public involvement (PPI) in health research, little emphasis has been placed on understanding its quality and appropriateness to evidence ...synthesis (ES) and systematic reviews (SR). This study aimed to synthesise qualitative evidence on the benefits, challenges, and best practices for PPI in ES/SR projects from the perspectives of patients/public and researchers.
Methods
We searched Ovid MEDLINE, Ovid EMBASE, Cochrane Library and CINAHL Plus. We also searched relevant grey literature and conducted hand‐searching to identify qualitative studies which report the benefits and challenges of PPI in individual ES/SR projects. Studies were independently screened by two reviewers for inclusion and appraised using the Joanna Briggs Institute's Qualitative Tool. Included studies were synthesised narratively using thematic synthesis.
Results
The literature search retrieved 9923 articles, of which eight studies were included in this review. Five themes on benefits emerged: two from patients'/public's perspective—gaining knowledge, and empowerment; and three from researchers' perspective—enhancing relevance, improving quality, and enhancing dissemination of findings. Six themes on challenges were identified: three from patients'/public's perspective—poor communication, time and low self‐esteem; and three from researchers' perspective—balancing inputs and managing relations, time, and resources and training. Concerning recommendations for best practice, four themes emerged: provision of sufficient time and resources, developing a clear recruitment plan, provision of sufficient training and support, and the need to foster positive working relationships.
Conclusion
Highlighting the benefits and challenges of PPI in ES/SR projects from different stakeholder perspectives is essential to understand the process and contextual factors and facilitate meaningful PPI in ES/SR projects. Future research should focus on the utilisation of existing frameworks (e.g., Authors and Consumers Together Impacting on eVidencE ACTIVE framework) by researchers to help describe and/or report the best approaches and methods for involving patients/public in ES/SRs projects.
Patient and Public Contribution
This review received great contributions from a recognised PPI partner, the Chair of the Cochrane Consumer Network Executive, to inform the final stage of the review (i.e., interpretation, publication and dissemination of findings). The PPI partner has been included as an author of this review.
The Joint Committee on Vaccination and Immunisation in the United Kingdom requested an evidence synthesis to investigate the relationship between asthma and coronavirus disease 2019 (COVID-19) ...outcomes.
We conducted a systematic review and meta-analysis to summarise evidence on the risk of severe COVID-19 outcomes in people with uncontrolled asthma or markers of asthma severity.
High-dose inhaled corticosteroids (ICS) or oral corticosteroids (OCS) were used as markers of asthma severity, following international or national asthma guidelines. Risk of bias was assessed using Joanna Briggs Institute tools. Adjusted point estimates were extracted for random-effects meta-analyses and subgroup analyses.
After screening, 12 studies (11 in adults and one in children) met the eligibility criteria. Adults using high-dose ICS or OCS had a pooled adjusted hazard ratio (aHR) of 1.33 (95% CI 1.06-1.67, I
=0%) for hospitalisation and an aHR of 1.22 (95% CI 0.90-1.65, I
=70%) for mortality for COVID-19. We found insufficient evidence for associations between markers on COVID-19 mortality in the subgroup analyses.
Adults with severe asthma are at increased risk of COVID-19 hospitalisation compared to nonusers. Our analysis highlighted the dearth of studies in children with asthma investigating serious COVID-19 outcomes.
COVID-19 has strained population breast mammography screening programs that aim to diagnose and treat breast cancers earlier. As the pandemic has affected countries differently, we aimed to quantify ...changes in breast screening volume and uptake during the first year of COVID-19 . We systematically searched Medline, the World Health Organization (WHO) COVID-19 database, and governmental databases. Studies covering January 2020 to March 2022 were included. We extracted and analyzed data regarding study methodology, screening volume, and uptake. To assess for risk of bias, we used the Joanna Briggs Institute (JBI) Critical Appraisal Tool. Twenty-six cross-sectional descriptive studies (focusing on 13 countries/nations) were included out of 935 independent records. Reductions in screening volume and uptake rates were observed among eight countries. Changes in screening participation volume in five nations with national population-based screening ranged from –13 to –31%. Among two countries with limited population-based programs, the decline ranged from –61 to –41%. Within the USA, population participation volumes varied ranging from +18 to –39%, with suggestion of differences by insurance status (HMO, Medicare, and low-income programs). Almost all studies had high risk of bias due to insufficient statistical analysis and confounding factors. The extent of COVID-19-induced reduction in breast screening participation volume differed by region and data suggested potential differences by healthcare setting (e.g., national health insurance vs. private healthcare). Recovery efforts should monitor access to screening and early diagnosis to determine whether prevention services need strengthening to increase the coverage of disadvantaged groups and reduce disparities.
Existing prevention and treatment strategies target the classic types of diabetes yet this approach might not always be appropriate in some settings where atypical phenotypes exist. This study aims ...to assess the socio-demographic and clinical characteristics of people with diabetes in rural Rwanda compared to those of urban dwellers.
A cross-sectional, clinic-based study was conducted in which individuals with diabetes mellitus were consecutively recruited from April 2015 to April 2016. Demographic and clinical data were collected from patient interviews, medical files and physical examinations. Chi-square tests and T-tests were used to compare proportions and means between rural and urban residents.
A total of 472 participants were recruited (mean age 40.2 ± 19.1 years), including 295 women and 315 rural residents. Compared to urban residents, rural residents had lower levels of education, were more likely to be employed in low-income work and to have limited access to running water and electricity. Diabetes was diagnosed at a younger age in rural residents (mean ± SD 32 ± 18 vs 41 ± 17 years; p < 0.001). Physical inactivity, family history of diabetes and obesity were significantly less prevalent in rural than in urban individuals (44% vs 66, 14.9% vs 28.7 and 27.6% vs 54.1%, respectively; p < 0.001). The frequency of fruit and vegetable consumption was lower in rural than in urban participants. High waist circumference was more prevalent in urban than in rural women and men (75.3% vs 45.5 and 30% vs 6%, respectively; p < 0.001). History of childhood under-nutrition was more frequent in rural than in urban individuals (22.5% vs 6.4%; p < 0.001).
Characteristics of people with diabetes in rural Rwanda appear to differ from those of individuals with diabetes in urban settings, suggesting that sub-types of diabetes exist in Rwanda. Generic guidelines for diabetes prevention and management may not be appropriate in different populations.
Orkney, north of mainland Scotland, has the world's highest prevalence of multiple sclerosis (MS); vitamin D deficiency, a marker of low UV exposure, is also common in Scotland. Strong associations ...have been identified between vitamin D deficiency and MS, and between UV exposure and MS independent of vitamin D, although causal relationships remain to be confirmed. We aimed to compare plasma 25-hydroxyvitamin D levels in Orkney and mainland Scotland, and establish the determinants of vitamin D status in Orkney. We compared mean vitamin D and prevalence of deficiency in cross-sectional study data from participants in the Orkney Complex Disease Study (ORCADES) and controls in the Scottish Colorectal Cancer Study (SOCCS). We used multivariable regression to identify factors associated with vitamin D levels in Orkney. Mean (standard deviation) vitamin D was significantly higher among ORCADES than SOCCS participants (35.3 (18.0) and 31.7 (21.2), respectively). Prevalence of severe vitamin D deficiency was lower in ORCADES than SOCCS participants (6.6% to 16.2% p = 1.1 x 10(-15)). Older age, farming occupations and foreign holidays were significantly associated with higher vitamin D in Orkney. Although mean vitamin D levels are higher in Orkney than mainland Scotland, this masks variation within the Orkney population which may influence MS risk.
The analysis of less common variants in genome-wide association studies promises to elucidate complex trait genetics but is hampered by low power to reliably detect association. We show that addition ...of population-specific exome sequence data to global reference data allows more accurate imputation, particularly of less common SNPs (minor allele frequency 1-10%) in two very different European populations. The imputation improvement corresponds to an increase in effective sample size of 28-38%, for SNPs with a minor allele frequency in the range 1-3%.
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