Publications by authors named "Igor Rudan"

468 Publications

Using evidence, expert opinion and epidemiological model to understand pathways to survival and mortality: The Pathways to Survival (PATHS) Tool.

J Glob Health 2021 12;11:15001. Epub 2021 Jun 12.

Health Nutrition and Population, The World Bank, Washington, DC, USA.

Background: The reasons why episodes of illness can lead to fatal outcomes in affected persons in low resource settings are numerous and complex. A tool that allows policy makers to better understand those complexities could be useful to improve success of programmes that are implemented globally to reduce mortality.

Methods: We developed a "Pathways to Survival" (PATHS) tool: an epidemiological model using decision trees, available evidence and expert opinion. PATHS visualises the "architecture" of mortality in the population by following the entire population cohort over a certain period of time. It explains how initially healthy persons progress through health systems to lethal outcomes at the end of the specified time period. We developed an illustrative example based on the 136 million newborns and an estimated 907 000 deaths from newborn sepsis in the year 2008. This allowed us to develop an epidemiological model that described pathways to deaths from neonatal sepsis globally in 2010.

Results: The model described the "status quo' situation in 2010 with 907 000 deaths to allow an assessment of the potential impact and feasibility of different interventions and programmes at various level of health systems in reducing this cause of mortality. A useful model should incorporate both a 'horizontal' and a 'vertical' component. The 'horizontal' would track the progress of all neonates globally through time, ie, their first 28 days of life, and separate them into different 'pathways' every time a change in their risk of dying from neonatal infection occurs because of their specific contextual circumstances. The 'vertical' would track their position within the health systems of their countries and separate them into different categories based on the ability of health system to intervene and reduce their risk of dying. Based on those requirements, PATHS tool was developed which is based on decision trees where different "branches" of the trees are associated with varying case-fatality rates.

Conclusions: The application of the PATHS tool on the example of newborn sepsis revealed that novel diagnostic tests could save many lives, so we should continue to invest in them to improve their validity, deliverability and affordability. However, PATHS showed that investments in better diagnostics have limited impact unless they are coupled with improvements of the context. Programs for parental education improve compliance and care seeking. Promoting legislation change to empower community health workers (CHWs) to actively engage in prevention, diagnosis and care also makes a difference, as well as programs for training CHWs to use diagnostic tests and administer treatments correctly. Care-seeking behaviour can also be improved through programs of conditional cash transfers. Finally, PATHS demonstrated that improving access to primary and secondary health care for everyone is the most powerful contextual change.
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http://dx.doi.org/10.7189/jogh.11.15001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8310575PMC
August 2021

Using evidence, expert opinion and epidemiological model to understand pathways to survival and mortality: The Pathways to Survival (PATHS) Tool.

J Glob Health 2021 12;11:15001. Epub 2021 Jun 12.

Health Nutrition and Population, The World Bank, Washington, DC, USA.

Background: The reasons why episodes of illness can lead to fatal outcomes in affected persons in low resource settings are numerous and complex. A tool that allows policy makers to better understand those complexities could be useful to improve success of programmes that are implemented globally to reduce mortality.

Methods: We developed a "Pathways to Survival" (PATHS) tool: an epidemiological model using decision trees, available evidence and expert opinion. PATHS visualises the "architecture" of mortality in the population by following the entire population cohort over a certain period of time. It explains how initially healthy persons progress through health systems to lethal outcomes at the end of the specified time period. We developed an illustrative example based on the 136 million newborns and an estimated 907 000 deaths from newborn sepsis in the year 2008. This allowed us to develop an epidemiological model that described pathways to deaths from neonatal sepsis globally in 2010.

Results: The model described the "status quo' situation in 2010 with 907 000 deaths to allow an assessment of the potential impact and feasibility of different interventions and programmes at various level of health systems in reducing this cause of mortality. A useful model should incorporate both a 'horizontal' and a 'vertical' component. The 'horizontal' would track the progress of all neonates globally through time, ie, their first 28 days of life, and separate them into different 'pathways' every time a change in their risk of dying from neonatal infection occurs because of their specific contextual circumstances. The 'vertical' would track their position within the health systems of their countries and separate them into different categories based on the ability of health system to intervene and reduce their risk of dying. Based on those requirements, PATHS tool was developed which is based on decision trees where different "branches" of the trees are associated with varying case-fatality rates.

Conclusions: The application of the PATHS tool on the example of newborn sepsis revealed that novel diagnostic tests could save many lives, so we should continue to invest in them to improve their validity, deliverability and affordability. However, PATHS showed that investments in better diagnostics have limited impact unless they are coupled with improvements of the context. Programs for parental education improve compliance and care seeking. Promoting legislation change to empower community health workers (CHWs) to actively engage in prevention, diagnosis and care also makes a difference, as well as programs for training CHWs to use diagnostic tests and administer treatments correctly. Care-seeking behaviour can also be improved through programs of conditional cash transfers. Finally, PATHS demonstrated that improving access to primary and secondary health care for everyone is the most powerful contextual change.
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http://dx.doi.org/10.7189/jogh.11.15001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8310575PMC
August 2021

Variants associated with expression have sex-differential effects on lung function.

Wellcome Open Res 2020 24;5:111. Epub 2021 May 24.

Centre for Genomic and Experimental Medicine, Institute of Genetics and Molecular Medicine, Western General Hospital, Edinburgh, EH4 2XU, UK.

Lung function is highly heritable and differs between the sexes throughout life. However, little is known about sex-differential genetic effects on lung function. We aimed to conduct the first genome-wide genotype-by-sex interaction study on lung function to identify genetic effects that differ between males and females. We tested for interactions between 7,745,864 variants and sex on spirometry-based measures of lung function in UK Biobank (N=303,612), and sought replication in 75,696 independent individuals from the SpiroMeta consortium. Five independent single-nucleotide polymorphisms (SNPs) showed genome-wide significant (P<5x10 ) interactions with sex on lung function, and 21 showed suggestive interactions (P<1x10 ). The strongest signal, from rs7697189 (chr4:145436894) on forced expiratory volume in 1 second (FEV ) (P=3.15x10 ), was replicated (P=0.016) in SpiroMeta. The C allele increased FEV more in males (untransformed FEV β=0.028 [SE 0.0022] litres) than females (β=0.009 [SE 0.0014] litres), and this effect was not accounted for by differential effects on height, smoking or pubertal age. rs7697189 resides upstream of the hedgehog-interacting protein ( ) gene and was previously associated with lung function and lung expression. We found expression was significantly different between the sexes (P=6.90x10 ), but we could not detect sex differential effects of rs7697189 on expression. We identified a novel genotype-by-sex interaction at a putative enhancer region upstream of the gene. Establishing the mechanism by which SNPs have different effects on lung function in males and females will be important for our understanding of lung health and diseases in both sexes.
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http://dx.doi.org/10.12688/wellcomeopenres.15846.2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7938335.2PMC
May 2021

The trans-ancestral genomic architecture of glycemic traits.

Nat Genet 2021 06 31;53(6):840-860. Epub 2021 May 31.

Department of Epidemiology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.

Glycemic traits are used to diagnose and monitor type 2 diabetes and cardiometabolic health. To date, most genetic studies of glycemic traits have focused on individuals of European ancestry. Here we aggregated genome-wide association studies comprising up to 281,416 individuals without diabetes (30% non-European ancestry) for whom fasting glucose, 2-h glucose after an oral glucose challenge, glycated hemoglobin and fasting insulin data were available. Trans-ancestry and single-ancestry meta-analyses identified 242 loci (99 novel; P < 5 × 10), 80% of which had no significant evidence of between-ancestry heterogeneity. Analyses restricted to individuals of European ancestry with equivalent sample size would have led to 24 fewer new loci. Compared with single-ancestry analyses, equivalent-sized trans-ancestry fine-mapping reduced the number of estimated variants in 99% credible sets by a median of 37.5%. Genomic-feature, gene-expression and gene-set analyses revealed distinct biological signatures for each trait, highlighting different underlying biological pathways. Our results increase our understanding of diabetes pathophysiology by using trans-ancestry studies for improved power and resolution.
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http://dx.doi.org/10.1038/s41588-021-00852-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7610958PMC
June 2021

Evaluating different national strategies to contain the COVID-19 pandemic before mass vaccination.

Authors:
Igor Rudan

J Glob Health 2021 May 15;11:01004. Epub 2021 May 15.

Centre for Global Health, the Usher Institute, The University of Edinburgh, Scotland, UK.

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http://dx.doi.org/10.7189/jogh.11.01004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8141329PMC
May 2021

The global prevalence of essential tremor, with emphasis on age and sex: A meta-analysis.

J Glob Health 2021 Apr 10;11:04028. Epub 2021 Apr 10.

Centre for Global Health, Usher Institute, University of Edinburgh, Edinburgh, UK.

Background: Essential tremor (ET) is one of the most common neurological disorders that impairs quality of life and leads to disability and social handicap. It was estimated that approximate 0.9% of people worldwide were affected by ET. The last decade has seen new investigations on the epidemiology of ET, enabling us to provide an up-to-date estimation of ET prevalence, with emphasis on age and sex.

Methods: We searched PubMed, Medline, Embase and Global Health for studies that reported the prevalence of ET in the general population. Potential sources of heterogeneity were examined by age-adjusted meta-regression. The age- and sex-specific prevalence of ET was constructed with a multilevel mixed-effects meta-regression.

Results: A total of 29 articles were included in our systematic review and meta-analysis. The prevalence of ET increased dramatically with advancing age, where the prevalence estimate in people aged under 20 years was 0.04% (95% confidence interval [CI] = 0.00-0.29) and that in elderly aged 80 years and above was 2.87% (95% CI = 1.07-7.49). ET was consistently more common in males than in females. In 2020, the overall prevalence of ET in the general population was 0.32% (95% CI = 0.12-0.91), and the prevalence was higher in males (0.36%, 95% CI = 0.14-1.03) than in females (0.28%, 95% CI = 0.11-0.79). In 2020, the number of people affected by ET was 24.91million (95% CI = 9.51-70.92), among whom 56% were males.

Conclusions: This study provides an up-to-date estimation of ET prevalence in the general population throughout the whole life span, with emphasis on age and sex. The adoption of an internationally acknowledged diagnostic strategy is prompted in future epidemiological investigations.

Protocol Registration: PROSPERO (CRD42020203979).
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http://dx.doi.org/10.7189/jogh.11.04028DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8035980PMC
April 2021

The COVID-19 pandemic: besides "post-truth" and "post-capitalism", should we also consider "post-education" and "post-reason"?

Authors:
Igor Rudan

J Glob Health 2021 Apr 3;11:01003. Epub 2021 Apr 3.

Centre for Global Health, The Usher Institute, The University of Edinburgh, Scotland, UK.

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http://dx.doi.org/10.7189/jogh.11.01003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8021072PMC
April 2021

The COVID-19 pandemic, proper science and everything else.

Authors:
Igor Rudan

J Glob Health 2021 Apr 3;11:01002. Epub 2021 Apr 3.

Centre for Global Health, the Usher Institute, The University of Edinburgh, Scotland, UK.

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http://dx.doi.org/10.7189/jogh.11.01002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8021075PMC
April 2021

The prevalence of adult attention-deficit hyperactivity disorder: A global systematic review and meta-analysis.

J Glob Health 2021 Feb 11;11:04009. Epub 2021 Feb 11.

Centre for Global Health Research, Usher Institute of Population Health Sciences and Informatics, University of Edinburgh, Edinburgh, UK.

Background: Adult attention-deficit hyperactivity disorder (ADHD) has recently attracted much attention, however, an up-to-date estimation on the prevalence of adult ADHD is lacking. In this study, we aimed to assess the global prevalence of adult ADHD in the general population through a systematic review and meta-analysis.

Methods: PubMed, Medline, Embase and PsycINFO were searched to identify relevant articles published from January 2000 onwards. Population-based studies that were conducted in the general adult population and quantified the prevalence of adult ADHD were included.

Results: The prevalence of persistent adult ADHD (with a childhood onset) and symptomatic adult ADHD (regardless of a childhood onset) both decreased with advancing age. By adjusting for the global demographic structure in 2020, the prevalence of persistent adult ADHD was 2.58% and that of symptomatic adult ADHD was 6.76%, translating to 139.84 million and 366.33 million affected adults in 2020 globally.

Conclusions: This study provides an up-to-date estimation of the global prevalence of both persistent and symptomatic adult ADHD. A well-defined strategy for diagnosing adult ADHD and large-scale investigations on the epidemiology of adult ADHD are needed.
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http://dx.doi.org/10.7189/jogh.11.04009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7916320PMC
February 2021

This is who to blame for the COVID-19 pandemic.

Authors:
Igor Rudan

J Glob Health 2021 Feb 11;11:03035. Epub 2021 Feb 11.

Centre for Global Health, Usher Institute, University of Edinburgh, Edinburgh, Scotland, UK.

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http://dx.doi.org/10.7189/jogh.11.03035DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7914402PMC
February 2021

Variation in the SERPINA6/SERPINA1 locus alters morning plasma cortisol, hepatic corticosteroid binding globulin expression, gene expression in peripheral tissues, and risk of cardiovascular disease.

J Hum Genet 2021 Jun 20;66(6):625-636. Epub 2021 Jan 20.

Centre for Global Health Research, Usher Institute, University of Edinburgh, Teviot Place, Edinburgh, EH8 9AG, Scotland.

The stress hormone cortisol modulates fuel metabolism, cardiovascular homoeostasis, mood, inflammation and cognition. The CORtisol NETwork (CORNET) consortium previously identified a single locus associated with morning plasma cortisol. Identifying additional genetic variants that explain more of the variance in cortisol could provide new insights into cortisol biology and provide statistical power to test the causative role of cortisol in common diseases. The CORNET consortium extended its genome-wide association meta-analysis for morning plasma cortisol from 12,597 to 25,314 subjects and from ~2.2 M to ~7 M SNPs, in 17 population-based cohorts of European ancestries. We confirmed the genetic association with SERPINA6/SERPINA1. This locus contains genes encoding corticosteroid binding globulin (CBG) and α1-antitrypsin. Expression quantitative trait loci (eQTL) analyses undertaken in the STARNET cohort of 600 individuals showed that specific genetic variants within the SERPINA6/SERPINA1 locus influence expression of SERPINA6 rather than SERPINA1 in the liver. Moreover, trans-eQTL analysis demonstrated effects on adipose tissue gene expression, suggesting that variations in CBG levels have an effect on delivery of cortisol to peripheral tissues. Two-sample Mendelian randomisation analyses provided evidence that each genetically-determined standard deviation (SD) increase in morning plasma cortisol was associated with increased odds of chronic ischaemic heart disease (0.32, 95% CI 0.06-0.59) and myocardial infarction (0.21, 95% CI 0.00-0.43) in UK Biobank and similarly in CARDIoGRAMplusC4D. These findings reveal a causative pathway for CBG in determining cortisol action in peripheral tissues and thereby contributing to the aetiology of cardiovascular disease.
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http://dx.doi.org/10.1038/s10038-020-00895-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8144017PMC
June 2021

Sex-dimorphic genetic effects and novel loci for fasting glucose and insulin variability.

Nat Commun 2021 01 5;12(1):24. Epub 2021 Jan 5.

Department of Biostatistics and Data Science, Division of Public Health Sciences, Wake Forest University School of Medicine, Winston-Salem, NC, USA.

Differences between sexes contribute to variation in the levels of fasting glucose and insulin. Epidemiological studies established a higher prevalence of impaired fasting glucose in men and impaired glucose tolerance in women, however, the genetic component underlying this phenomenon is not established. We assess sex-dimorphic (73,089/50,404 women and 67,506/47,806 men) and sex-combined (151,188/105,056 individuals) fasting glucose/fasting insulin genetic effects via genome-wide association study meta-analyses in individuals of European descent without diabetes. Here we report sex dimorphism in allelic effects on fasting insulin at IRS1 and ZNF12 loci, the latter showing higher RNA expression in whole blood in women compared to men. We also observe sex-homogeneous effects on fasting glucose at seven novel loci. Fasting insulin in women shows stronger genetic correlations than in men with waist-to-hip ratio and anorexia nervosa. Furthermore, waist-to-hip ratio is causally related to insulin resistance in women, but not in men. These results position dissection of metabolic and glycemic health sex dimorphism as a steppingstone for understanding differences in genetic effects between women and men in related phenotypes.
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http://dx.doi.org/10.1038/s41467-020-19366-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7785747PMC
January 2021

Systematic review estimating the burden of dementia in the WHO Southeast Asia Region using Bayesian and frequentist approaches.

J Glob Health 2020 Dec;10(2):020701

Centre for Global Health Research, Usher Institute of Population Health Sciences and Informatics, University of Edinburgh, UK.

Background: Rapid increase in life expectancy in low- and middle-income countries including the World Health Organization's Southeast Asia Region (SEAR) has resulted in an increase in the global burden of dementia, which is expected to become a leading cause of morbidity. Accurate burden estimates are key for informing policy and planning. Given the paucity of data, estimates were developed using both a Bayesian methodology and as well as a traditional frequentist approach to gain better insights into methodological approaches for disease burden estimates.

Methods: Seven databases were searched for studies published between 2010-2018 regarding dementia prevalence in SEAR, generating 8 relevant articles. A random-effects model (REM) and a Bayesian normal-normal hierarchical model (NNHM) were used to obtain the pooled prevalence estimate of dementia for people aged 60 and above in SEAR. The latter model was also developed to estimate age-specific dementia prevalence. Using UN population estimates for SEAR, total and age-specific projections of the burden of dementia in 2015, 2020 and 2030 were calculated.

Results: The prevalence of dementia in SEAR was found to be 3% (95% confidence interval (CI) = 2-6%) in those above age 60 based on REM, and 3.1% (95% credible interval = 1.5-5.0%) based on the NNHM. The estimated prevalence varies with age, increasing from 1.6% (95% credible interval = 0.8-2.5%) in people aged 60-69 to 12.4% (95% credible interval = 5.6-20%) in people above the age of 80. The risk of developing dementia increased exponentially with age. The number of people living with dementia in SEAR in 2015 was estimated at 5.51 million (95% credible interval = 2.66-8.82), with projections of 6.66 million (95% credible interval = 3.21-10.7) in 2020 and 9.6 million (95% credible interval = 4.62-15.36) in 2030.

Conclusion: The burden of dementia in SEAR is substantial and will continue to increase rapidly by 2030. The lack of research focusing on dementia in SEAR points to a significant under-recognition of this disease. The projected rise in dementia cases in the future should prompt urgent governmental response to address this growing public health issue. We also argue that given the overall paucity of data for the region, the Bayesian approach offers a promising methodology for improved estimates of disease prevalence and burden and should continue to be explored.
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http://dx.doi.org/10.7189/jogh.10.020701DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7688200PMC
December 2020

Discovery of rare variants associated with blood pressure regulation through meta-analysis of 1.3 million individuals.

Nat Genet 2020 12 23;52(12):1314-1332. Epub 2020 Nov 23.

Department of Clinical Biochemistry, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev, Denmark.

Genetic studies of blood pressure (BP) to date have mainly analyzed common variants (minor allele frequency > 0.05). In a meta-analysis of up to ~1.3 million participants, we discovered 106 new BP-associated genomic regions and 87 rare (minor allele frequency ≤ 0.01) variant BP associations (P < 5 × 10), of which 32 were in new BP-associated loci and 55 were independent BP-associated single-nucleotide variants within known BP-associated regions. Average effects of rare variants (44% coding) were ~8 times larger than common variant effects and indicate potential candidate causal genes at new and known loci (for example, GATA5 and PLCB3). BP-associated variants (including rare and common) were enriched in regions of active chromatin in fetal tissues, potentially linking fetal development with BP regulation in later life. Multivariable Mendelian randomization suggested possible inverse effects of elevated systolic and diastolic BP on large artery stroke. Our study demonstrates the utility of rare-variant analyses for identifying candidate genes and the results highlight potential therapeutic targets.
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http://dx.doi.org/10.1038/s41588-020-00713-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7610439PMC
December 2020

Answering 20 more questions on COVID-19 (March-April 2020).

Authors:
Igor Rudan

J Glob Health 2020 Dec;10(2):020102

Centre for Global Health, Usher Institute for Population Health Sciences and Informatics, The University of Edinburgh, Scotland, UK.

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http://dx.doi.org/10.7189/jogh.10.020102DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7506195PMC
December 2020

A strategy to incorporate prior knowledge into correlation network cutoff selection.

Nat Commun 2020 10 14;11(1):5153. Epub 2020 Oct 14.

Institute of Computational Biology, Helmholtz Center Munich - German Research Center for Environmental Health, 85764, Neuherberg, Germany.

Correlation networks are frequently used to statistically extract biological interactions between omics markers. Network edge selection is typically based on the statistical significance of the correlation coefficients. This procedure, however, is not guaranteed to capture biological mechanisms. We here propose an alternative approach for network reconstruction: a cutoff selection algorithm that maximizes the overlap of the inferred network with available prior knowledge. We first evaluate the approach on IgG glycomics data, for which the biochemical pathway is known and well-characterized. Importantly, even in the case of incomplete or incorrect prior knowledge, the optimal network is close to the true optimum. We then demonstrate the generalizability of the approach with applications to untargeted metabolomics and transcriptomics data. For the transcriptomics case, we demonstrate that the optimized network is superior to statistical networks in systematically retrieving interactions that were not included in the biological reference used for optimization.
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http://dx.doi.org/10.1038/s41467-020-18675-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7560866PMC
October 2020

Genome-wide association study identifies 48 common genetic variants associated with handedness.

Nat Hum Behav 2021 01 28;5(1):59-70. Epub 2020 Sep 28.

Institute of Biological Psychiatry, Mental Health Services of Copenhagen, Copenhagen, Denmark.

Handedness has been extensively studied because of its relationship with language and the over-representation of left-handers in some neurodevelopmental disorders. Using data from the UK Biobank, 23andMe and the International Handedness Consortium, we conducted a genome-wide association meta-analysis of handedness (N = 1,766,671). We found 41 loci associated (P < 5 × 10) with left-handedness and 7 associated with ambidexterity. Tissue-enrichment analysis implicated the CNS in the aetiology of handedness. Pathways including regulation of microtubules and brain morphology were also highlighted. We found suggestive positive genetic correlations between left-handedness and neuropsychiatric traits, including schizophrenia and bipolar disorder. Furthermore, the genetic correlation between left-handedness and ambidexterity is low (r = 0.26), which implies that these traits are largely influenced by different genetic mechanisms. Our findings suggest that handedness is highly polygenic and that the genetic variants that predispose to left-handedness may underlie part of the association with some psychiatric disorders.
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http://dx.doi.org/10.1038/s41562-020-00956-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7116623PMC
January 2021

Global variability of the human IgG glycome.

Aging (Albany NY) 2020 08 12;12(15):15222-15259. Epub 2020 Aug 12.

Institute of Clinical Biochemistry, Priština, Kosovo.

Immunoglobulin G (IgG) is the most abundant serum antibody which structural characteristics and effector functions are modulated through the attachment of various sugar moieties called glycans. Composition of the IgG N-glycome changes with age of an individual and in different diseases. Variability of IgG glycosylation within a population is well studied and is known to be affected by both genetic and environmental factors. However, global inter-population differences in IgG glycosylation have never been properly addressed. Here we present population-specific N-glycosylation patterns of IgG, analyzed in 5 different populations totaling 10,482 IgG glycomes, and of IgG's fragment crystallizable region (Fc), analyzed in 2,579 samples from 27 populations sampled across the world. Country of residence associated with many N-glycan features and the strongest association was with monogalactosylation where it explained 38% of variability. IgG monogalactosylation strongly correlated with the development level of a country, defined by United Nations health and socioeconomic development indicators, and with the expected lifespan. Subjects from developing countries had low levels of IgG galactosylation, characteristic for inflammation and ageing. Our results suggest that citizens of developing countries may be exposed to environmental factors that can cause low-grade chronic inflammation and the apparent increase in biological age.
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http://dx.doi.org/10.18632/aging.103884DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7467356PMC
August 2020

Systematic Evaluation of Normalization Methods for Glycomics Data Based on Performance of Network Inference.

Metabolites 2020 Jul 2;10(7). Epub 2020 Jul 2.

Department of Physiology and Biophysics, Institute for Computational Biomedicine, Englander Institute for Precision Medicine, Weill Cornell Medicine, New York, NY 10022, USA.

Glycomics measurements, like all other high-throughput technologies, are subject to technical variation due to fluctuations in the experimental conditions. The removal of this non-biological signal from the data is referred to as normalization. Contrary to other omics data types, a systematic evaluation of normalization options for glycomics data has not been published so far. In this paper, we assess the quality of different normalization strategies for glycomics data with an innovative approach. It has been shown previously that Gaussian Graphical Models (GGMs) inferred from glycomics data are able to identify enzymatic steps in the glycan synthesis pathways in a data-driven fashion. Based on this finding, here, we quantify the quality of a given normalization method according to how well a GGM inferred from the respective normalized data reconstructs known synthesis reactions in the glycosylation pathway. The method therefore exploits a biological measure of goodness. We analyzed 23 different normalization combinations applied to six large-scale glycomics cohorts across three experimental platforms: Liquid Chromatography - ElectroSpray Ionization - Mass Spectrometry (LC-ESI-MS), Ultra High Performance Liquid Chromatography with Fluorescence Detection (UHPLC-FLD), and Matrix Assisted Laser Desorption Ionization - Furier Transform Ion Cyclotron Resonance - Mass Spectrometry (MALDI-FTICR-MS). Based on our results, we recommend normalizing glycan data using the 'Probabilistic Quotient' method followed by log-transformation, irrespective of the measurement platform. This recommendation is further supported by an additional analysis, where we ranked normalization methods based on their statistical associations with age, a factor known to associate with glycomics measurements.
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http://dx.doi.org/10.3390/metabo10070271DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7408386PMC
July 2020

Linking protein to phenotype with Mendelian Randomization detects 38 proteins with causal roles in human diseases and traits.

PLoS Genet 2020 07 6;16(7):e1008785. Epub 2020 Jul 6.

MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Western General Hospital, Edinburgh, Scotland, United Kingdom.

To efficiently transform genetic associations into drug targets requires evidence that a particular gene, and its encoded protein, contribute causally to a disease. To achieve this, we employ a three-step proteome-by-phenome Mendelian Randomization (MR) approach. In step one, 154 protein quantitative trait loci (pQTLs) were identified and independently replicated. From these pQTLs, 64 replicated locally-acting variants were used as instrumental variables for proteome-by-phenome MR across 846 traits (step two). When its assumptions are met, proteome-by-phenome MR, is equivalent to simultaneously running many randomized controlled trials. Step 2 yielded 38 proteins that significantly predicted variation in traits and diseases in 509 instances. Step 3 revealed that amongst the 271 instances from GeneAtlas (UK Biobank), 77 showed little evidence of pleiotropy (HEIDI), and 92 evidence of colocalization (eCAVIAR). Results were wide ranging: including, for example, new evidence for a causal role of tyrosine-protein phosphatase non-receptor type substrate 1 (SHPS1; SIRPA) in schizophrenia, and a new finding that intestinal fatty acid binding protein (FABP2) abundance contributes to the pathogenesis of cardiovascular disease. We also demonstrated confirmatory evidence for the causal role of four further proteins (FGF5, IL6R, LPL, LTA) in cardiovascular disease risk.
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http://dx.doi.org/10.1371/journal.pgen.1008785DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7337286PMC
July 2020

Answering the initial 20 questions on COVID-19 (January-February 2020).

Authors:
Igor Rudan

J Glob Health 2020 Jun;10(1):010106

Centre for Global Health, Usher Institute, The University of Edinburgh, Scotland, UK.

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http://dx.doi.org/10.7189/jogh.10.010106DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7303804PMC
June 2020

Multi-ancestry GWAS of the electrocardiographic PR interval identifies 202 loci underlying cardiac conduction.

Nat Commun 2020 05 21;11(1):2542. Epub 2020 May 21.

Wellcome Centre for Human Genetics, University of Oxford, Oxford, UK.

The electrocardiographic PR interval reflects atrioventricular conduction, and is associated with conduction abnormalities, pacemaker implantation, atrial fibrillation (AF), and cardiovascular mortality. Here we report a multi-ancestry (N = 293,051) genome-wide association meta-analysis for the PR interval, discovering 202 loci of which 141 have not previously been reported. Variants at identified loci increase the percentage of heritability explained, from 33.5% to 62.6%. We observe enrichment for cardiac muscle developmental/contractile and cytoskeletal genes, highlighting key regulation processes for atrioventricular conduction. Additionally, 8 loci not previously reported harbor genes underlying inherited arrhythmic syndromes and/or cardiomyopathies suggesting a role for these genes in cardiovascular pathology in the general population. We show that polygenic predisposition to PR interval duration is an endophenotype for cardiovascular disease, including distal conduction disease, AF, and atrioventricular pre-excitation. These findings advance our understanding of the polygenic basis of cardiac conduction, and the genetic relationship between PR interval duration and cardiovascular disease.
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http://dx.doi.org/10.1038/s41467-020-15706-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7242331PMC
May 2020

Gene-educational attainment interactions in a multi-ancestry genome-wide meta-analysis identify novel blood pressure loci.

Mol Psychiatry 2020 May 5. Epub 2020 May 5.

Health Disparities Research Section, Laboratory of Epidemiology and Population Sciences, National Institute on Aging, National Institutes of Health, Baltimore, MD, 21224, USA.

Educational attainment is widely used as a surrogate for socioeconomic status (SES). Low SES is a risk factor for hypertension and high blood pressure (BP). To identify novel BP loci, we performed multi-ancestry meta-analyses accounting for gene-educational attainment interactions using two variables, "Some College" (yes/no) and "Graduated College" (yes/no). Interactions were evaluated using both a 1 degree of freedom (DF) interaction term and a 2DF joint test of genetic and interaction effects. Analyses were performed for systolic BP, diastolic BP, mean arterial pressure, and pulse pressure. We pursued genome-wide interrogation in Stage 1 studies (N = 117 438) and follow-up on promising variants in Stage 2 studies (N = 293 787) in five ancestry groups. Through combined meta-analyses of Stages 1 and 2, we identified 84 known and 18 novel BP loci at genome-wide significance level (P < 5 × 10). Two novel loci were identified based on the 1DF test of interaction with educational attainment, while the remaining 16 loci were identified through the 2DF joint test of genetic and interaction effects. Ten novel loci were identified in individuals of African ancestry. Several novel loci show strong biological plausibility since they involve physiologic systems implicated in BP regulation. They include genes involved in the central nervous system-adrenal signaling axis (ZDHHC17, CADPS, PIK3C2G), vascular structure and function (GNB3, CDON), and renal function (HAS2 and HAS2-AS1, SLIT3). Collectively, these findings suggest a role of educational attainment or SES in further dissection of the genetic architecture of BP.
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http://dx.doi.org/10.1038/s41380-020-0719-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7641978PMC
May 2020

Global and regional prevalence, burden, and risk factors for carotid atherosclerosis: a systematic review, meta-analysis, and modelling study.

Lancet Glob Health 2020 05;8(5):e721-e729

Centre for Global Health Research, Usher Institute of Population Health Sciences and Informatics, University of Edinburgh, Edinburgh, UK.

Background: Estimation of the epidemiological burden of carotid atherosclerosis can serve as a basis for prevention and management of cardiovascular disease. We aimed to provide the first estimation on the prevalence, number of cases, and risk factors for carotid atherosclerosis in the general population globally and regionally.

Methods: In this systematic review, meta-analysis, and modelling study, we searched PubMed, MEDLINE, Embase, Global Health, and China National Knowledge Infrastructure for articles published from database inception until May 7, 2019, with no language restrictions, for population-based studies that quantified prevalence of carotid atherosclerosis by means of increased carotid intima-media thickness, carotid plaque, and carotid stenosis. Studies were eligible if they included bilaterally scanned carotid arteries using ultrasonography and defined increased carotid intima-media thickness as a thickness of 1·0 mm or more, carotid plaque as a focal carotid intima-media thickness of 1·5 mm or more encroaching into the lumen or at least 0·5 mm or 50% compared with the surrounding carotid intima-media thickness values, and carotid stenosis as 50% or more stenosis. Studies were excluded if the sample was not representative of the general population. We also included studies identified in our previous systematic review and meta-analysis of the prevalence of carotid atherosclerosis in China. We estimated age-specific and sex-specific prevalences of increased carotid intima-media thickness, carotid plaque, and carotid stenosis. We used UN population data to generate the number of people affected in 2000, 2015, and 2020. We did random-effects meta-analyses to assess the effects of risk factors for increased carotid intima-media thickness and carotid plaque. We derived regional numbers of people living with increased carotid intima-media thickness and carotid plaque in 2015 using a risk factors-based model by WHO region. All analyses were done in populations aged 30-79 years due to availability of data. This systematic review and meta-analysis is registered online on PROSPERO, CRD42019134709.

Findings: We identified 8632 articles through our database search, of which 515 were eligible for full-text review, including 37 articles from our previous study, and 59 articles were eligible for inclusion in our systematic review and meta-analysis. Overall, in people aged 30-79 years in 2020, the global prevalence of increased carotid intima-media thickness is estimated to be 27·6% (95% CI 16·9-41·3), equivalent to 1066·70 million affected people and a percentage change of 57·46% from 2000; of carotid plaque is estimated to be 21·1% (13·2-31·5), equivalent to 815·76 million affected people and a percentage change of 58·97% from 2000; and carotid stenosis is estimated to be 1·5% (1·1-2·1), equivalent to 57·79 million affected people and a percentage change of 59·13% from 2000. The prevalence of increased carotid intima-media thickness, carotid plaque, and carotid stenosis increased consistently with age and was higher in men than in women. Current smoking, diabetes, and hypertension were common risk factors for increased carotid intima-media thickness and carotid plaque. In 2015, the Western Pacific region had the largest share of global cases of increased carotid intima-media thickness (317·62 million [33·36%] of 952·13 million affected people) and carotid plaque (240·77 million [33·20%] of 725·25 million), whereas the African region had the smallest share of cases of increased carotid intima-media thickness (59·08 million [6·21%]) and the Eastern Mediterranean region had the smallest share of carotid plaque cases (44·59 million [6·15%]).

Interpretation: A substantial global burden of carotid atherosclerosis exists. Effective strategies are needed for primary prevention and management of carotid atherosclerosis. High-quality epidemiological investigations on carotid atherosclerosis are needed to better address the global burden of carotid atherosclerosis at finer levels.

Funding: None.
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http://dx.doi.org/10.1016/S2214-109X(20)30117-0DOI Listing
May 2020

Helping global health topics go viral online.

J Glob Health 2020 Jun;8(1):010101

Centre for Global Health Research, Usher Institute for Population Health Sciences and Informatics, The University of Edinburgh, Scotland, UK.

To maintain support for further investments into health research and prevent large groups of people from questioning modern science, researchers will increasingly need to master their communication of scientific progress in the 21st century to broad general population. The new generations, who inform and educate themselves online, prefer to make their own choices in what they view. This makes them vulnerable to many types of online misinformation, which is placed there mainly to attract their clicks. This evolving context could strongly undermine a consensus in the population over very important public health issues and gains. Therefore, we believe that it deserves to be recognised as a serious problem of our time that needs to be addressed. In addition to possible inaccuracies of the health information found online, the other component of the problem is how to make global public health topics and issues attractive for viewing online and engaging with. They need to compete with popular music, celebrity gossip, sports, movies and other forms of entertainment. In this issue, we bring a novel series aiming to explore effective strategies to promoting global health issues online and through other mass media, and reaching wide audiences.
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http://dx.doi.org/10.7189/jogh.10-010101DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7100623PMC
June 2020

Effective approaches to public engagement with global health topics.

J Glob Health 2020 Jun;10(1):01040901

Centre for Global Health, Usher Institute, University of Edinburgh, Edinburgh, Scotland, UK.

Background: "Public engagement" in science is a term that covers a broad spectrum of activities undertaken by the scientific community. The precise definitions are constantly evolving to incorporate new means of engagement, facilitated by emerging technologies. Global health research is amenable to community engagement and popularization, but it is difficult to know which strategies work best to attract considerable attention from the public.

Methods: This is a review of the articles and documents that address the question of public engagement with topics in medical sciences, particularly in global health. Semantic searches were conducted using Google Scholar rather than indexed databases due to poor indexing of the topic. More than 1000 titles were screened and 48 articles were retained as most useful. It then moves to a more specific topic of the online public engagement in global health.

Results: The review presents the attempts to define public engagement in science and its general importance, particularly in the field of global health. Examples of the latter include tobacco use, vaccination, and maternal and child health. In reviewing effective approaches to public engagement in global health through online video campaigns, it studies the examples of crowdfunding, USAID's First Public Engagement Campaign, World Health Organization's Social Media Campaigns and the impact of Global Health Media Project.

Conclusions: This review reveals three key gaps in the understanding of determinants of effective online public engagement in global health. The mixed results of traditional mass media campaigns in global health emphasise the calls for more research on message content. A framework for effective message content would help in both raising awareness of key issues and creating behaviour change in the general public. Moreover, it is surprising to find no formal research on what constitutes effective video content in global health. Finally, few studies considered important metrics to track in social media campaigns. There is a clear need to investigate which video features are effective in global health online public engagement. Success will be defined through key video marketing metrics and tracked in order to isolate effective content features.
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http://dx.doi.org/10.7189/jogh.10.010901DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7101214PMC
June 2020

A systematic analysis of online public engagement with 10 videos on major global health topics involving 229 459 global online viewers.

J Glob Health 2020 Jun;10(1):010903

Centre for Global Health, Usher Institute for Informatics and Population Sciences, University of Edinburgh, Edinburgh, Scotland, UK.

Background: Online interest in issues specific to global health outside of times of pandemics or other crises is rather limited. To achieve long term global health goals, public support and engagement needs to be fostered on a continual basis. Strategies for capturing the attention of the general public online for the persisting problems outside of emergency situations are poorly defined. There are only a few isolated examples of success. In this study we explored the engagement of the viewers with different global health topics that were provided on public and privately advertised YouTube channels.

Methods: We developed the Massive Open Online Course "Survival: The Story of Global Health", consisting of 10 educational videos on major global health topics. We conducted two experiments in two separate samples of viewers. The first was based on posting videos on a YouTube channel between August 30 and September 30, 2017 and collecting analytics on the viewership. By June 30, 2019 this approach attracted 41 305 viewers. The second experiment was more controlled and conducted on a private YouTube channel and the videos were advertised to reach a high number of viewers. This attracted 188 154 viewers and we collected data on viewers' behaviour using YouTube Analytics. We investigated the nature of engagement, which was defined by 22 different parameters.

Results: In the first experiment, there were clear differences in all measured parameters of engagement based on the topic of the video. Episodes on pandemics (14 594 views) and human evolution (10 761 views) were clear outliers, while the remaining 8 episodes received between 1110 and 3197 views. In the second experiment, there were several clear differences between the 10 videos in the parameters analysed through YouTube Analytics. Episode 2 on maternal and child health had the highest view rate (18.90%), followed by Episode 7 on international organisations in global health (16.83%). At the bottom of the rank were Episode 6 on ageing and dying (view rate of 13.83%) and Episode 5 on non-communicable diseases (view rate 14.59%).

Conclusions: We determined that 5 main interdependent factors contributed to the success or failure of our global health videos: Responsive content, timing, contribution to public debate, emotional valency and endorsement from an authentic scientific voice with a strong public profile. Several of these factors are also recognised as important in marketing research which may indicate the value of such techniques for use in a global health context. In order to communicate long term sustainable solutions to complex issues in a capricious media landscape focused on transient issues the global health community needs to embrace novel marketing approaches.
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http://dx.doi.org/10.7189/jogh.10.010903DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7101210PMC
June 2020

Analysis of public engagement with ten major global health topics on a social network profile and a newspaper website.

J Glob Health 2020 Jun;10(1):010902

Centre for Global Health, Usher Institute for Informatics and Population Sciences, University of Edinburgh, Edinburgh, Scotland, UK.

Background: Efforts in global health and development have broad political support and substantial financial commitment from most governments. However, this support could be greater if global health issues featured more prominently in the public debate. It has proven quite difficult to make global health issues attractive for viewing and engaging with, as compared to other forms of entertainment or public debates in the media.

Methods: Within the Massive Open Online Course "Survival: The Story of Global Health", we created 10 educational videos on major global health topics. Between August 1 and September 30, 2017, we posted each episode with a brief background text on the Facebook profile of the narrator, who had an average of 450 friends and further 800 followers throughout the period of study. We studied the interaction of Facebook friends and followers with each posted video, tracing the number of their "likes", "shares" and "comments". Moreover, a popular Croatian online newspaper portal with about 250 000 daily viewers shared three of these stories after they were posted on Facebook and views, shares and comments were monitored. We recorded the effect on the number of YouTube views of the featured videos.

Results: The 10 posts received between 65 and 274 "likes" on the Facebook profile and between 2 and 124 shares, receiving between 0 and 17 comments. The three episodes that were shared by the online newspaper portal were further shared between 164 and 2820 times, receiving between 8 and 111 comments from the general public. The effect of these two promotion channels on YouTube viewership resulted in between 107 and 9784 views of the 10 featured videos, with the number of "likes" received on YouTube ranging between 0 and 43. The video that raised the most attention and shares was the one on the history of pandemics, which also had the highest number of shares on YouTube (n=69), followed by the video on human evolution (n = 14). Topics of non-communicable diseases, ageing and dying, and the future of humanity were also popular, while the topics more specific to global health raised less interest - ie, maternal and child mortality, major infectious diseases, international organizations, inequality and equity, and the UN Millennium Development Goals.

Conclusion: Our study showed that the interest in "core" global health topics was, as a rule, lower than in the topics which have a more general appeal - such as pandemic threat, human origins, ageing and dying. If we aim to increase public interest in global health topics, a feasible strategy would be to adjust the language and presentation used to be of more appeal to popular culture. Linking promotional materials to other popular topics that are dominating the public debate or capturing their interest could prove to be a successful strategy to achieve this.
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http://dx.doi.org/10.7189/jogh.10.010902DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7101213PMC
June 2020
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