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- Wang, Haidong, et al.
(författare)
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Global, regional, and national life expectancy, all-cause mortality, and cause-specific mortality for 249 causes of death, 1980-2015 : a systematic analysis for the Global Burden of Disease Study 2015
- 2016
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Ingår i: The Lancet. - 0140-6736 .- 1474-547X. ; 388:10053, s. 1459-1544
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Improving survival and extending the longevity of life for all populations requires timely, robust evidence on local mortality levels and trends. The Global Burden of Disease 2015 Study (GBD 2015) provides a comprehensive assessment of all-cause and cause-specific mortality for 249 causes in 195 countries and territories from 1980 to 2015. These results informed an in-depth investigation of observed and expected mortality patterns based on sociodemographic measures.METHODS: We estimated all-cause mortality by age, sex, geography, and year using an improved analytical approach originally developed for GBD 2013 and GBD 2010. Improvements included refinements to the estimation of child and adult mortality and corresponding uncertainty, parameter selection for under-5 mortality synthesis by spatiotemporal Gaussian process regression, and sibling history data processing. We also expanded the database of vital registration, survey, and census data to 14 294 geography-year datapoints. For GBD 2015, eight causes, including Ebola virus disease, were added to the previous GBD cause list for mortality. We used six modelling approaches to assess cause-specific mortality, with the Cause of Death Ensemble Model (CODEm) generating estimates for most causes. We used a series of novel analyses to systematically quantify the drivers of trends in mortality across geographies. First, we assessed observed and expected levels and trends of cause-specific mortality as they relate to the Socio-demographic Index (SDI), a summary indicator derived from measures of income per capita, educational attainment, and fertility. Second, we examined factors affecting total mortality patterns through a series of counterfactual scenarios, testing the magnitude by which population growth, population age structures, and epidemiological changes contributed to shifts in mortality. Finally, we attributed changes in life expectancy to changes in cause of death. We documented each step of the GBD 2015 estimation processes, as well as data sources, in accordance with Guidelines for Accurate and Transparent Health Estimates Reporting (GATHER).FINDINGS: Globally, life expectancy from birth increased from 61·7 years (95% uncertainty interval 61·4-61·9) in 1980 to 71·8 years (71·5-72·2) in 2015. Several countries in sub-Saharan Africa had very large gains in life expectancy from 2005 to 2015, rebounding from an era of exceedingly high loss of life due to HIV/AIDS. At the same time, many geographies saw life expectancy stagnate or decline, particularly for men and in countries with rising mortality from war or interpersonal violence. From 2005 to 2015, male life expectancy in Syria dropped by 11·3 years (3·7-17·4), to 62·6 years (56·5-70·2). Total deaths increased by 4·1% (2·6-5·6) from 2005 to 2015, rising to 55·8 million (54·9 million to 56·6 million) in 2015, but age-standardised death rates fell by 17·0% (15·8-18·1) during this time, underscoring changes in population growth and shifts in global age structures. The result was similar for non-communicable diseases (NCDs), with total deaths from these causes increasing by 14·1% (12·6-16·0) to 39·8 million (39·2 million to 40·5 million) in 2015, whereas age-standardised rates decreased by 13·1% (11·9-14·3). Globally, this mortality pattern emerged for several NCDs, including several types of cancer, ischaemic heart disease, cirrhosis, and Alzheimer's disease and other dementias. By contrast, both total deaths and age-standardised death rates due to communicable, maternal, neonatal, and nutritional conditions significantly declined from 2005 to 2015, gains largely attributable to decreases in mortality rates due to HIV/AIDS (42·1%, 39·1-44·6), malaria (43·1%, 34·7-51·8), neonatal preterm birth complications (29·8%, 24·8-34·9), and maternal disorders (29·1%, 19·3-37·1). Progress was slower for several causes, such as lower respiratory infections and nutritional deficiencies, whereas deaths increased for others, including dengue and drug use disorders. Age-standardised death rates due to injuries significantly declined from 2005 to 2015, yet interpersonal violence and war claimed increasingly more lives in some regions, particularly in the Middle East. In 2015, rotaviral enteritis (rotavirus) was the leading cause of under-5 deaths due to diarrhoea (146 000 deaths, 118 000-183 000) and pneumococcal pneumonia was the leading cause of under-5 deaths due to lower respiratory infections (393 000 deaths, 228 000-532 000), although pathogen-specific mortality varied by region. Globally, the effects of population growth, ageing, and changes in age-standardised death rates substantially differed by cause. Our analyses on the expected associations between cause-specific mortality and SDI show the regular shifts in cause of death composition and population age structure with rising SDI. Country patterns of premature mortality (measured as years of life lost [YLLs]) and how they differ from the level expected on the basis of SDI alone revealed distinct but highly heterogeneous patterns by region and country or territory. Ischaemic heart disease, stroke, and diabetes were among the leading causes of YLLs in most regions, but in many cases, intraregional results sharply diverged for ratios of observed and expected YLLs based on SDI. Communicable, maternal, neonatal, and nutritional diseases caused the most YLLs throughout sub-Saharan Africa, with observed YLLs far exceeding expected YLLs for countries in which malaria or HIV/AIDS remained the leading causes of early death.INTERPRETATION: At the global scale, age-specific mortality has steadily improved over the past 35 years; this pattern of general progress continued in the past decade. Progress has been faster in most countries than expected on the basis of development measured by the SDI. Against this background of progress, some countries have seen falls in life expectancy, and age-standardised death rates for some causes are increasing. Despite progress in reducing age-standardised death rates, population growth and ageing mean that the number of deaths from most non-communicable causes are increasing in most countries, putting increased demands on health systems.
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| 2. |
- Xiao, Qingyang
(författare)
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Facilitating precision medicine through analysis of next-generation sequencing projects
- 2020
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Precision medicine constitutes an emerging strategy that aims at the individualization of healthcare by considering the personal molecular features and environmental factors of the patient in question. Genetic biomarkers constitute one dimension of a patient’s molecular phenotype that can allow for treatment stratification. As such, incorporating genetic variability into clinical decision making has raised great interest with drug developers, regulators and in the wider medical community. Importantly however, most studies that evaluated associations of genetic variability with drug reponse or toxicity interrogated only selected, mostly common candidate variants and the prevalence and relevance of rare variants for pharmacogenetics remained largely unexplored. This thesis demonstrates how population-scale Next-Generation Sequencing (NGS) data can be leveraged to map the interindividual and ethnogeographic variability of genes with medical importance. Papers I and II focused on ATP-binding casette (ABC) transporters, as an example of a pharmacogenetically relevant gene family, and show how their variability can have potential predictive value in breast cancer chemotherpy. The human ABC transporter family consists of 48 functionally important membrane proteins which mediate the active transport of a plethora of substrates, including a multitude of endogenous substrates as well as drugs, such as calcium channel blockers and various chemotherapeutics. Because of this physiological and clinical importance, Paper I systematically investigated the interindividual and ethnogeographic variability in the ABC transporter superfamily using NGS data of 138,632 unrelated individuals worldwide, and used an list of sophisticated computational algorithms to estimate their functional relevance. In total, 62,793 exonic variants were discovered, of which 98.5% were rare with minor allele frequencies (MAF) <1.5%. Based on these data, individuals were found to harbor between 9.3 and 13.9 deleterious ABC variants, only 0.3% of which were shared among all populations. As such, this work analyzed the landscape of ABC transporter variability on an unprecedented scale and revealed large interindividual and ethnogeographic variability with potential relevance for the treatment with ABC transporter substrates. Paper II built on these findings by evaluating whether ABC transporter variability was associated with drug response. As drug resistance due to facilitated ABC transporter-mediated efflux of chemotherapeutics constitutes an important cause of morbidity and mortality, ABC transporter variability was evaluated whether it could predict treatment outcomes in breast invasive carcinoma (BRCA), clear cell renal carcinoma (ccRCC) and hepatocellular carcinoma (HCC). In contrast to previous studies, these analyses did not only consider common ABC polymorphisms but considered also rare genetic variants using mutational burden testing. Importantly, variant burden of ABCC1 was found to significantly assoiate with reduced survival in BRCA patients, specifically in those subgroups treated with the MRP1 (the transporter encoded by ABCC1) 2 substrates doxorubicin (p=0.0088) and cyclophosphamide (p=0.0011). In contrast, no association was discovered in tamoxifen-treated patients (p=0.13). Multiple variants enriched in the high mutational burden group affected residues in functionally important transporter domains providing additional mechanistic support. Combined, these results argue for a model in which multiple variants with individually small effect sizes shape drug resistance, thus incentivizing a shift in strategy away from the interrogation of candidate variants and towards the incorporation of germline data for precision cancer medicine. Paper III indicated how publically available sequencing data from individuals can be used to provide accurate estimates of population-specific carrier rates and genetic complexity of 450 human autosomal recessive (AR) diseases. Specifically, population-scale NGS data of individuals free from clinically diagnosed congenital disorders was used to identify disease allele carrier frequencies for 450 AR disorders. Using 85 diseases with known epidemiology, the data showed that our prevalence estimates corresponded well to clinically reported incidences (p<0.001; R=0.68). Furthermore, these data allowed for the first time to evaluate the genetic complexity of the human AR diseasome and estimate population-specific founder effects. As such, these analyses reveal the molecular genetics of AR diseases with unprecedented resolution and provide important insights into epidemiology, complexity and population-specific founder effects, which can provide a powerful resource for clinical geneticists to inform population-adjusted genetic screening programs, particularly in otherwise understudied ethnogeographic groups. In conclusion, by utilizing sophisticated computational methods for the analysis of publically available population-scale sequencing data of >130,000 individuals, this thesis uncovered the landscape of genetic variability in genes with importance for pharmacogenetics and congenital disease. The resulting findings aspire to improve pharmacogenetic interpretations and carrier screening programs and, hopefully, can contribute to the advancement of precision medicine.
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