Time intervals from first symptom to treatment of cancer: a cohort study of 2,212 newly diagnosed cancer patients

<p>Abstract</p> <p>Background</p> <p>Delay in diagnosis of cancer may worsen prognosis. The aim of this study is to explore patient-, general practitioner (GP)- and system-related delay in the interval from first cancer symptom to diagnosis and treatment, and to analyse the extent to which delays differ by cancer type.</p> <p>Methods</p> <p>Population-based cohort study conducted in 2004-05 in the County of Aarhus, Denmark (640,000 inhabitants). Data were collected from administrative registries and questionnaires completed by GPs on 2,212 cancer patients newly diagnosed during a 1-year period. Median delay (in days) with interquartile interval (IQI) was the main outcome measure.</p> <p>Results</p> <p>Median total delay was 98 days (IQI 57-168). Most of the total delay stemmed from patient (median 21 days (7-56)) and system delay (median 55 days (32-93)). Median GP delay was 0 (0-2) days. Total delay was shortest among patients with ovarian (median 60 days (45-112)) and breast cancer (median 65 days (39-106)) and longest among patients with prostate (median 130 days (89-254)) and bladder cancer (median 134 days (93-181)).</p> <p>Conclusion</p> <p>System delay accounted for a substantial part of the total delay experienced by cancer patients. This points to a need for shortening clinical pathways if possible. A long patient delay calls for research into patient awareness of cancer. For all delay components, special focus should be given to the 4^thquartile of patients with the longest time intervals and we need research into the quality of the diagnostic work-up process. We found large variations in delay for different types of cancer. Improvements should therefore target both the population at large and the specific needs associated with individual cancer types and their symptoms.</p

Hundreds of variants clustered in genomic loci and biological pathways affect human height

Most common human traits and diseases have a polygenic pattern of inheritance: DNA sequence variants at many genetic loci influence the phenotype. Genome-wide association (GWA) studies have identified more than 600 variants associated with human traits, but these typically explain small fractions of phenotypic variation, raising questions about the use of further studies. Here, using 183,727 individuals, we show that hundreds of genetic variants, in at least 180 loci, influence adult height, a highly heritable and classic polygenic trait. The large number of loci reveals patterns with important implications for genetic studies of common human diseases and traits. First, the 180 loci are not random, but instead are enriched for genes that are connected in biological pathways (P = 0.016) and that underlie skeletal growth defects (P < 0.001). Second, the likely causal gene is often located near the most strongly associated variant: in 13 of 21 loci containing a known skeletal growth gene, that gene was closest to the associated variant. Third, at least 19 loci have multiple independently associated variants, suggesting that allelic heterogeneity is a frequent feature of polygenic traits, that comprehensive explorations of already-discovered loci should discover additional variants and that an appreciable fraction of associated loci may have been identified. Fourth, associated variants are enriched for likely functional effects on genes, being over-represented among variants that alter amino-acid structure of proteins and expression levels of nearby genes. Our data explain approximately 10% of the phenotypic variation in height, and we estimate that unidentified common variants of similar effect sizes would increase this figure to approximately 16% of phenotypic variation (approximately 20% of heritable variation). Although additional approaches are needed to dissect the genetic architecture of polygenic human traits fully, our findings indicate that GWA studies can identify large numbers of loci that implicate biologically relevant genes and pathways.

Genome-wide association study identifies six new loci influencing pulse pressure and mean arterial pressure.

Numerous genetic loci have been associated with systolic blood pressure (SBP) and diastolic blood pressure (DBP) in Europeans. We now report genome-wide association studies of pulse pressure (PP) and mean arterial pressure (MAP). In discovery (N = 74,064) and follow-up studies (N = 48,607), we identified at genome-wide significance (P = 2.7 × 10(-8) to P = 2.3 × 10(-13)) four new PP loci (at 4q12 near CHIC2, 7q22.3 near PIK3CG, 8q24.12 in NOV and 11q24.3 near ADAMTS8), two new MAP loci (3p21.31 in MAP4 and 10q25.3 near ADRB1) and one locus associated with both of these traits (2q24.3 near FIGN) that has also recently been associated with SBP in east Asians. For three of the new PP loci, the estimated effect for SBP was opposite of that for DBP, in contrast to the majority of common SBP- and DBP-associated variants, which show concordant effects on both traits. These findings suggest new genetic pathways underlying blood pressure variation, some of which may differentially influence SBP and DBP

Idiopathic pulmonary fibrosis - a systematic review on methodology for the collection of epidemiological data

Peer reviewe

Genetic variants in novel pathways influence blood pressure and cardiovascular disease risk.

Blood pressure is a heritable trait influenced by several biological pathways and responsive to environmental stimuli. Over one billion people worldwide have hypertension (≥140 mm Hg systolic blood pressure or  ≥90 mm Hg diastolic blood pressure). Even small increments in blood pressure are associated with an increased risk of cardiovascular events. This genome-wide association study of systolic and diastolic blood pressure, which used a multi-stage design in 200,000 individuals of European descent, identified sixteen novel loci: six of these loci contain genes previously known or suspected to regulate blood pressure (GUCY1A3-GUCY1B3, NPR3-C5orf23, ADM, FURIN-FES, GOSR2, GNAS-EDN3); the other ten provide new clues to blood pressure physiology. A genetic risk score based on 29 genome-wide significant variants was associated with hypertension, left ventricular wall thickness, stroke and coronary artery disease, but not kidney disease or kidney function. We also observed associations with blood pressure in East Asian, South Asian and African ancestry individuals. Our findings provide new insights into the genetics and biology of blood pressure, and suggest potential novel therapeutic pathways for cardiovascular disease prevention

Multi-ancestry genome-wide association analyses improve resolution of genes and pathways influencing lung function and chronic obstructive pulmonary disease risk.

Lung-function impairment underlies chronic obstructive pulmonary disease (COPD) and predicts mortality. In the largest multi-ancestry genome-wide association meta-analysis of lung function to date, comprising 580,869 participants, we identified 1,020 independent association signals implicating 559 genes supported by ≥2 criteria from a systematic variant-to-gene mapping framework. These genes were enriched in 29 pathways. Individual variants showed heterogeneity across ancestries, age and smoking groups, and collectively as a genetic risk score showed strong association with COPD across ancestry groups. We undertook phenome-wide association studies for selected associated variants as well as trait and pathway-specific genetic risk scores to infer possible consequences of intervening in pathways underlying lung function. We highlight new putative causal variants, genes, proteins and pathways, including those targeted by existing drugs. These findings bring us closer to understanding the mechanisms underlying lung function and COPD, and should inform functional genomics experiments and potentially future COPD therapies

A Low-Frequency Inactivating Akt2 Variant Enriched in the Finnish Population is Associated With Fasting Insulin Levels and Type 2 Diabetes Risk

To identify novel coding association signals and facilitate characterization of mechanisms influencing glycemic traits and type 2 diabetes risk, we analyzed 109,215 variants derived from exome array genotyping together with an additional 390,225 variants from exome sequence in up to 39,339 normoglycemic individuals from five ancestry groups. We identified a novel association between the coding variant (p.Pro50Thr) in AKT2 and fasting insulin, a gene in which rare fully penetrant mutations are causal for monogenic glycemic disorders. The low-frequency allele is associated with a 12% increase in fasting plasma insulin (FI) levels. This variant is present at 1.1% frequency in Finns but virtually absent in individuals from other ancestries. Carriers of the FI-increasing allele had increased 2-hour insulin values, decreased insulin sensitivity, and increased risk of type 2 diabetes (odds ratio=1.05). In cellular studies, the AKT2-Thr50 protein exhibited a partial loss of function. We extend the allelic spectrum for coding variants in AKT2 associated with disorders of glucose homeostasis and demonstrate bidirectional effects of variants within the pleckstrin homology domain of AKT2.Academy of Finland (129293, 128315, 129330, 131593, 139635, 139635, 121584, 126925, 124282, 129378, 258753); Action on Hearing Loss (G51); Ahokas Foundation; American Diabetes Association (#7-12-MN-02); Atlantic Canada Opportunities Agency; Augustinus foundation; Becket foundation; Benzon Foundation; Biomedical Research Council; British Heart Foundation (SP/04/002); Canada Foundation for Innovation; Commission of the European Communities, Directorate C-Public Health (2004310); Copenhagen County; Danish Centre for Evaluation and Health Technology Assessment; Danish Council for Independent Research; Danish Heart Foundation (07-10-R61-A1754-B838-22392F); Danish Medical Research Council; Danish Pharmaceutical Association; Emil Aaltonen Foundation; European Research Council Advanced Research Grant; European Union FP7 (EpiMigrant, 279143; FP7/2007-2013; 259749); Finland's Slottery Machine Association; Finnish Cultural Foundation; Finnish Diabetes Research Foundation; Finnish Foundation for Cardiovascular Research; Finnish Foundation of Cardiovascular Research; Finnish Medical Society; Finnish National Public Health Institute; Finska Läkaresällskapet; Folkhälsan Research Foundation; Foundation for Life and Health in Finland; German Center for Diabetes Research (DZD) ; German Federal Ministry of Education and Research; Health Care Centers in Vasa, Närpes and Korsholm; Health Insurance Foundation (2012B233) ; Helsinki University Central Hospital Research Foundation; Hospital districts of Pirkanmaa, Southern Ostrobothnia, North Ostrobothnia, Central Finland, and Northern Savo; Ib Henriksen foundation; Juho Vainio Foundation; Korea Centers for Disease Control and Prevention (4845–301); Korea National Institute of Health (2012-N73002-00); Li Ka Shing Foundation; Liv och Hälsa; Lundbeck Foundation; Marie-Curie Fellowship (PIEF-GA-2012-329156); Medical Research Council (G0601261, G0900747-91070, G0601966, G0700931); Ministry of Education in Finland; Ministry of Social Affairs and Health in Finland; MRC-PHE Centre for Environment and Health;Municipal Heath Care Center and Hospital in Jakobstad; Närpes Health Care Foundation; National Institute for Health Research (RP-PG-0407-10371); National Institutes of Health (U01 DK085526, U01 DK085501, U01 DK085524, U01 DK085545, U01 DK085584, U01 DK088389, RC2-DK088389, DK085545, DK098032, HHSN268201300046C, HHSN268201300047C, HHSN268201300048C, HHSN268201300049C, HHSN, R01MH107666 and K12CA139160268201300050C, U01 DK062370, R01 DK066358, U01DK085501, R01HL102830, R01DK073541, PO1AG027734, R01AG046949, 1R01AG042188, P30AG038072, R01 MH101820, R01MH090937, P30DK020595, R01 DK078616, NIDDK K24 DK080140, 1RC2DK088389, T32GM007753); National Medical Research Council; National Research Foundation of Korea (NRF-2012R1A2A1A03006155); Nordic Center of Excellence in Disease Genetics; Novo Nordisk; Ollqvist Foundation; OrionFarmos Research Foundation; Paavo Nurmi Foundation; Perklén Foundation; Samfundet Folkhälsan; Signe and Ane Gyllenberg Foundation; Sigrid Juselius Foundation; Social Insurance Institution of Finland; South East Norway Health Authority (2011060); Swedish Cultural Foundation in Finland; Swedish Heart-Lung Foundation; Swedish Research Council; Swedish Research Council (Linné and Strategic Research Grant); The American Federation for Aging Research; The Einstein Glenn Center; The European Commission (HEALTH-F4-2007-201413); The Finnish Diabetes Association; The Folkhälsan Research Foundation; The Påhlssons Foundation; The provinces of Newfoundland and Labrador, Nova Scotia, and New Brunswick; The Sigrid Juselius Foundation; The Skåne Regional Health Authority; The Swedish Heart-Lung Foundation; Timber Merchant Vilhelm Bang’s Foundation; Turku University Foundation; Uppsala University; Wellcome Trust (064890, 083948, 085475, 086596, 090367, 090532, 092447, 095101/Z/10/Z, 200837/Z/16/Z, 095552, 098017, 098381, 098051, 084723, 072960/2/ 03/2, 086113/Z/08/Z, WT098017, WT064890, WT090532, WT098017, 098051, WT086596/Z/08/A and 086596/Z/08/Z). Detailed acknowledgment of funding sources is provided in the Additional Acknowledgements section of the Supplementary Materials

Genome-wide association study identifies 74 loci associated with educational attainment

Educational attainment is strongly influenced by social and other environmental factors, but genetic factors are estimated to account for at least 20% of the variation across individuals1. Here we report the results of a genome-wide association study (GWAS) for educational attainment that extends our earlier discovery sample1,2 of 101,069 individuals to 293,723 individuals, and a replication study in an independent sample of 111,349 individuals from the UK Biobank. We identify 74 genome-wide significant loci associated with the number of years of schooling completed. Single-nucleotide polymorphisms associated with educational attainment are disproportionately found in genomic regions regulating gene expression in the fetal brain. Candidate genes are preferentially expressed in neural tissue, especially during the prenatal period, and enriched for biological pathways involved in neural development. Our findings demonstrate that, even for a behavioural phenotype that is mostly environmentally determined, a well-powered GWAS identifies replicable associated genetic variants that suggest biologically relevant pathways. Because educational attainment is measured in large numbers of individuals, it will continue to be useful as a proxy phenotype in efforts to characterize the genetic influences of related phenotypes, including cognition and neuropsychiatric diseases

Diminishing benefits of urban living for children and adolescents’ growth and development

AbstractOptimal growth and development in childhood and adolescence is crucial for lifelong health and well-being1–6. Here we used data from 2,325 population-based studies, with measurements of height and weight from 71 million participants, to report the height and body-mass index (BMI) of children and adolescents aged 5–19 years on the basis of rural and urban place of residence in 200 countries and territories from 1990 to 2020. In 1990, children and adolescents residing in cities were taller than their rural counterparts in all but a few high-income countries. By 2020, the urban height advantage became smaller in most countries, and in many high-income western countries it reversed into a small urban-based disadvantage. The exception was for boys in most countries in sub-Saharan Africa and in some countries in Oceania, south Asia and the region of central Asia, Middle East and north Africa. In these countries, successive cohorts of boys from rural places either did not gain height or possibly became shorter, and hence fell further behind their urban peers. The difference between the age-standardized mean BMI of children in urban and rural areas was &lt;1.1 kg m–2 in the vast majority of countries. Within this small range, BMI increased slightly more in cities than in rural areas, except in south Asia, sub-Saharan Africa and some countries in central and eastern Europe. Our results show that in much of the world, the growth and developmental advantages of living in cities have diminished in the twenty-first century, whereas in much of sub-Saharan Africa they have amplified.</jats:p