A pooled testing strategy for identifying SARS-CoV-2 at low prevalence

Suppressing infections of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) will probably require the rapid identification and isolation of individuals infected with the virus on an ongoing basis. Reverse-transcription polymerase chain reaction (RT-PCR) tests are accurate but costly, which makes the regular testing of every individual expensive. These costs are a challenge for all countries around the world, but particularly for low-to-middle-income countries. Cost reductions can be achieved by pooling (or combining) subsamples and testing them in groups1-7. A balance must be struck between increasing the group size and retaining test sensitivity, as sample dilution increases the likelihood of false-negative test results for individuals with a low viral load in the sampled region at the time of the test8. Similarly, minimizing the number of tests to reduce costs must be balanced against minimizing the time that testing takes, to reduce the spread of the infection. Here we propose an algorithm for pooling subsamples based on the geometry of a hypercube that, at low prevalence, accurately identifies individuals infected with SARS-CoV-2 in a small number of tests and few rounds of testing. We discuss the optimal group size and explain why, given the highly infectious nature of the disease, largely parallel searches are preferred. We report proof-of-concept experiments in which a positive subsample was detected even when diluted 100-fold with negative subsamples (compared with 30-48-fold dilutions described in previous studies9-11). We quantify the loss of sensitivity due to dilution and discuss how it may be mitigated by the frequent re-testing of groups, for example. With the use of these methods, the cost of mass testing could be reduced by a large factor. At low prevalence, the costs decrease in rough proportion to the prevalence. Field trials of our approach are under way in Rwanda and South Africa. The use of group testing on a massive scale to monitor infection rates closely and continually in a population, along with the rapid and effective isolation of people with SARS-CoV-2 infections, provides a promising pathway towards the long-term control of coronavirus disease 2019 (COVID-19).info:eu-repo/semantics/publishe

A Mendelian randomization study of genetic liability to post-traumatic stress disorder and risk of ischemic stroke.

Observational studies have shown an association between post-traumatic stress disorder (PTSD) and ischemic stroke (IS) but given the susceptibility to confounding it is unclear if these associations represent causal effects. Mendelian randomization (MR) facilitates causal inference that is robust to the influence of confounding. Using two sample MR, we investigated the causal effect of genetic liability to PTSD on IS risk. Ancestry-specific genetic instruments of PTSD and four quantitative sub-phenotypes of PTSD, including hyperarousal, avoidance, re-experiencing, and total symptom severity score (PCL-Total) were obtained from the Million Veteran Programme (MVP) using a threshold P value (P) of <5 × 10-7, clumping distance of 1000 kilobase (Mb) and r2 < 0.01. Genetic association estimates for IS were obtained from the MEGASTROKE consortium (Ncases = 34,217, Ncontrols = 406,111) for European ancestry individuals and from the Consortium of Minority Population Genome-Wide Association Studies of Stroke (COMPASS) (Ncases = 3734, Ncontrols = 18,317) for African ancestry individuals. We used the inverse-variance weighted (IVW) approach as the main analysis and performed MR-Egger and the weighted median methods as pleiotropy-robust sensitivity analyses. In European ancestry individuals, we found evidence of an association between genetic liability to PTSD avoidance, and PCL-Total and increased IS risk (odds ratio (OR)1.04, 95% Confidence Interval (CI) 1.007-1.077, P = 0.017 for avoidance and (OR 1.02, 95% CI 1.010-1.040, P = 7.6 × 10-4 for PCL total). In African ancestry individuals, we found evidence of an association between genetically liability to PCL-Total and reduced IS risk (OR 0.95 (95% CI 0.923-0.991, P = 0.01) and hyperarousal (OR 0.83 (95% CI 0.691-0.991, P = 0.039) but no association was observed for PTSD case-control, avoidance, or re-experiencing. Similar estimates were obtained with MR sensitivity analyses. Our findings suggest that specific sub-phenotypes of PTSD, such as hyperarousal, avoidance, PCL total, may have a causal effect on people of European and African ancestry's risk of IS. This shows that the molecular mechanisms behind the relationship between IS and PTSD may be connected to symptoms of hyperarousal and avoidance. To clarify the precise biological mechanisms involved and how they may vary between populations, more research is required

OVERVIEW OF PRE-CLINICAL TECHNIQUES FOR PREDICTING THE IMMUNOGENICITY OF THERAPEUTICS IN DRUG DEVELOPEMENT

Immunogenicity testing is a vital component of drug development as it leads to drugs that are safer and more effective. This review provides an overview of the pre-clinical models that can be used to predict the immunogenic potential of novel protein therapeutics prior to administration in humans. Tools important for the prediction of the immunogenicity of protein therapeutics include animal models, in vitro cell assays, and in silico techniques. Animal models including rodents, transgenic mice, and non-human primates are reviewed. Among the immunoinformatics tools commonly used to predict immunogenicity include the Structural Epitope Database, Immune Epitope Database and Analysis Resource (IEDB), The MHCBN database, Dana-Farber Repository for Machine Learning in Immunology, and TEPITOPE. Identifiation and subsequent removal or inhibition of epitopes and MHC agretopes minimizes immunogenicity. Strategies for minimization of immunogenicity in biotherapeutics including epitope and MHC agretope removal, improvement of solubility, derivatization with polyethylene glycol (PEG), and use of chimeric antibodies are also discussed. Immunogenicity testing is an important part of the drug development process as it leads to drugs that are safer and more effective. Animal models including rodents, transgenic mice, and non-human primates; in vitro cell assays; and immunoinformatics tools are used to identify epitopes and MHC agretopes which are then eliminated or inhibited so as to minimize immunogenicity

Tobacco use and associated factors among Rwandan youth aged 15-34 years: Findings from a nationwide survey, 2013.

IntroductionUse of tobacco and its products are the single most preventable cause of death in the world. The objective of this study was to determine the prevalence of current tobacco use and identify associated factors among Rwandans aged 15-34 years.MethodsThis study involved secondary analysis of existing data from the nationally representative WHO STEPwise approach to Surveillance of non-communicable diseases (STEPS) conducted in 2013 to explore the prevalence of tobacco use and its associated factors in Rwanda. Data of 3,900 youth participants (15-34 years old) who had been selected using multistage cluster sampling during the survey was analyzed. The prevalence of current smoking along with socio-demographic characteristics of the sample were determined and multivariable logistic regression was employed to identify independent factors associated with current tobacco use.ResultsThe prevalence (weighted) of current tobacco use (all forms) was 8% (95%CI: 7.08-9.01). The prevalence was found to be significantly higher among males, young adults aged 24-34, youth with primary school education or less, those from Southern province, people with income (work in public, private organizations and self-employed) and young married adults. However, geographical location i.e. urban (7%) and rural (8%) settings did not affect prevalence of tobacco use. Factors that were found to be associated with current tobacco use through the multivariate analysis included being male, aged 25 years and above, having an income, and residing in Eastern, Kigali City and Southern Province compared to Western province.ConclusionThe association between smoking and socio-demographic characteristics among Rwandan youth identified in this study provides an opportunity for policy makers to tailor future tobacco control policies, and implement coordinated, high-impact interventions to prevent initiation of tobacco use among the youth

OC 8526 THE RWANDA CLINICAL RESEARCH NETWORK (RWANDA-CRN): A MODEL FOR MIXED SOUTH-SOUTH AND NORTH-SOUTH COLLABORATIONS FOR CLINICAL RESEARCH CAPACITY DEVELOPMENT

BackgroundPoor countries carry 90% of the global burden of disease, with access to only 10% of globally available health research funding and technical capacity. Fragile south–south collaborations hinder effective use of limited resources, career opportunities and funding to retain the insufficiently available quality scientists. The Rwanda Health System established a clinical research network involving academia, non-governmental organisations and private sector to accelerate generation of talented scientists, create enabling environment and incentives to retain scientists by establishing a local funding model.MethodsBased on a baseline assessment, potential clinical trial units were mapped and developed through adoption of a Clinical trial management training model from European Universities. The Rwandan law on Public Private Partnership was leveraged to attract and engage local and international private players in a win-win approach. So far, countries such as Kenya and Sweden were engaged in the roadmap.ResultsFrom 2014 to date, a total of 285 scientists are trained on various clinical research components: Good Clinical Practice (28%), Research Grant writing (14%), systematic review and meta-analysis (9%) and scientific communication (8.7%). Ten Clinical Research Units and one centre for evidence-based healthcare were established. So far 13 health investigator-initiated projects in malaria, metabolic disorders and maternal health were funded through the local funding model. A process to empower six malaria sentinel sites into fully functioning clinical research sites is underway.ConclusionThe creation of strong networks of excellence forclinical research among southern academic, research institutions and pharmaceutical and non-pharmaceutical industry is a promising strategic approach to promote sustainable clinical research capacity. The government vision is that beyond national boundaries, resource sharing and involvement of private players are key factors to mitigate the high burden of disease, nationally and regionally.</jats:sec

Building skills and resources for genomics, epigenetics, and bioinformatics research for Africa: Report of the joint 11th conference of the african society of human genetics and 12th H3 Africa consortium, 2018

The 11th Congress of the African Society of Human Genetics (AfSHG) was held from September 16, 2018 to September 21, 2018, in conjunction with the 12th Human Heredity and Health in Africa (H3Africa) Consortium meeting in Kigali, Rwanda. The event was organized by the AfSHG in partnership with the Rwanda Society of Human Genetics and the University of Rwanda. A 2-day workshop on the application of next-generation sequencing technologies for analyzing monogenic disease in African populations was organized as part of the conference (September 22, 2018-September 23, 2018, Kigali, Rwanda). The theme of the conference was "Building skills and resources for genomics, epigenetics and bioinformatics research for Africa."The conference served as a platform to bring together members from country-specific Societies of Human Genetics, including Rwanda, Cameroon, Democratic Republic of Congo, Egypt, Mali, Senegal, and South Africa, and included 435 delegates from 38 countries, including 29 African countries that attended the conference. A major topic of discussion was how to bridge the gap between the emerging knowledge on genomics and Omics in African populations. The importance of understanding the role of genetic variation in disease causation and susceptibility among Africans was a constant theme during the meeting, as was the need to develop research infrastructure and resources to enhance healthcare systems, so that they are not left behind in the genomic revolution. It was concluded that there is a need to inspire more African scientists to train and work as investigators, clinicians, and genetic counselors in the field of human genetics in Africa. Local investments, and South-South and South-North collaboration were identified as the key drivers for the successful implementation of research and development on the continent.SCOPUS: ar.jinfo:eu-repo/semantics/publishe

Author Correction: A pooled testing strategy for identifying SARS-CoV-2 at low prevalence (Nature, (2021), 589, 7841, (276-280), 10.1038/s41586-020-2885-5)

In Fig. 2 of this Article, the Ct values for the orf1ab gene (shown in Fig. 2b) in samples B16121 and B16122 at 20×, 50× and 100× dilution were accidental duplications of those of the N gene (shown in Fig. 2a). The Ct values for orf1ab have been corrected in Fig. 2 of the original Article, and Fig. 1 of this Amendment shows the original and corrected Fig. 2b, for transparency. As B16121 and B16122 are both low-Ct samples, this change has no effect on our conclusion that typical samples are easily detected after 100-fold dilution. In Extended Data Table 2 of this Article, which presents the source data for Fig. 2, the orf1ab Ct values for sample B16121 were incorrectly given as 29, 29.74 and 30.54 for 20×, 50× and 100× dilution, respectively, instead of 31, 30.51 and 30.95, respectively. In addition, the orf1ab Ct values for sample B16122 were incorrectly given as 26.81, 27.75 and 29.07 for 20×, 50× and 100× dilution, respectively, instead of 28.5, 29.4 and 30.2, respectively. Extended Data Table 2 of the original Article has been corrected online. We thank T. Carey for drawing this error to our attention. The original Article has been corrected online. (Figure presented.).SCOPUS: er.jinfo:eu-repo/semantics/publishe