Statistical analysis in the German National Cohort (NAKO) - specific aspects and general recommendations

The German National Cohort (NAKO) is an ongoing, prospective multicenter cohort study, which started recruitment in 2014 and includes more than 205,000 women and men aged 19-74 years. The study data will be available to the global research community for analyses. Although the ultimate decision about the analytic methods will be made by the respective investigator, in this paper we provide the basis for a harmonized approach to the statistical analyses in the NAKO. We discuss specific aspects of the study (e.g., data collection, weighting to account for the sampling design), but also give general recommendations which may apply to other large cohort studies as well

Grip strength values and cut-off points based on over 200,000 adults of the German National Cohort - a comparison to the EWGSOP2 cut-off points

BACKGROUND: The European Working Group on Sarcopenia in Older People (EWGSOP) updated in 2018 the cut-off points for low grip strength to assess sarcopenia based on pooled data from 12 British studies. OBJECTIVE: Comparison of the EWGSOP2 cut-off points for low grip strength to those derived from a large German sample. METHODS: We assessed the grip strength distribution across age and derived low grip strength cut-off points for men and women (peak mean -2.5 × SD) based on 200,389 German National Cohort (NAKO) participants aged 19-75 years. In 1,012 Cooperative Health Research in the Region of Augsburg (KORA)-Age participants aged 65-93 years, we calculated the age-standardised prevalence of low grip strength and time-dependent sensitivity and specificity for all-cause mortality. RESULTS: Grip strength increased in the third and fourth decade of life and declined afterwards. Calculated cut-off points for low grip strength were 29 kg for men and 18 kg for women. In KORA-Age, the age-standardised prevalence of low grip strength was 1.5× higher for NAKO-derived (17.7%) compared to EWGSOP2 (11.7%) cut-off points. NAKO-derived cut-off points yielded a higher sensitivity and lower specificity for all-cause mortality. CONCLUSIONS: Cut-off points for low grip strength from German population-based data were 2 kg higher than the EWGSOP2 cut-off points. Higher cut-off points increase the sensitivity, thereby suggesting an intervention for more patients at risk, while other individuals might receive additional diagnostics/treatment without the urgent need. Research on the effectiveness of intervention in patients with low grip strength defined by different cut-off points is needed

Occupation and SARS-CoV-2 infection risk among 108 960 workers during the first pandemic wave in Germany

OBJECTIVE: The aim of this study was to identify the occupational risk for a SARS-CoV-2 infection in a nationwide sample of German workers during the first wave of the COVID-19 pandemic (1 February-31 August 2020). METHODS: We used the data of 108 960 workers who participated in a COVID follow-up survey of the German National Cohort (NAKO). Occupational characteristics were derived from the German Classification of Occupations 2010 (Klassifikation der Berufe 2010). PCR-confirmed SARS-CoV-2 infections were assessed from self-reports. Incidence rates (IR) and incidence rate ratios (IRR) were estimated using robust Poisson regression, adjusted for person-time at risk, age, sex, migration background, study center, working hours, and employment relationship. RESULTS: The IR was 3.7 infections per 1000 workers [95% confidence interval (CI) 3.3-4.1]. IR differed by occupational sector, with the highest rates observed in personal (IR 4.8, 95% CI 4.0-5.6) and business administration (IR 3.4, 95% CI 2.8-3.9) services and the lowest rates in occupations related to the production of goods (IR 2.0, 95% CI 1.5-2.6). Infections were more frequent among essential workers compared with workers in non-essential occupations (IRR 1.95, 95% CI 1.59-2.40) and among highly skilled compared with skilled professions (IRR 1.36, 95% CI 1.07-1.72). CONCLUSIONS: The results emphasize higher infection risks in essential occupations and personal-related services, especially in the healthcare sector. Additionally, we found evidence that infections were more common in higher occupational status positions at the beginning of the pandemic

Design und Qualitätskontrolle der zahnmedizinischen Untersuchung in der NAKO Gesundheitsstudie [Design and quality control of the oral health status examination in the German National Cohort (GNC)]

BACKGROUND: Caries and periodontitis are highly prevalent worldwide. Because detailed data on these oral diseases were collected within the framework of the German National Cohort (GNC), associations between oral and systemic diseases and conditions can be investigated. OBJECTIVES: The study protocol for the oral examination was designed to ensure a comprehensive collection of dental findings by trained non-dental staff within a limited examination time. At the mid-term of the GNC baseline examination, a first quality evaluation was performed to check the plausibility of results and to propose measures to improve the data quality. MATERIALS AND METHODS: A dental interview, saliva sampling and oral diagnostics were conducted. As part of the level‑1 examination, the number of teeth and prostheses were recorded. As part of the level‑2 examination, detailed periodontal, cariological and functional aspects were examined. All examinations were conducted by trained non-dental personnel. Parameters were checked for plausibility and variable distributions were descriptively analysed. RESULTS: Analyses included data of 57,967 interview participants, 56,913 level‑1 participants and 6295 level‑2 participants. Percentages of missing values for individual clinical parameters assessed in level 1 and level 2 ranged between 0.02 and 3.9%. Results showed a plausible distribution of the data; rarely, implausible values were observed, e.g. for measurements of horizontal and vertical overbite (overjet and overbite). Intra-class correlation coefficients indicated differences in individual parameters between regional clusters, study centres and across different examiners. CONCLUSIONS: he results confirm the feasibility of the study protocol by non-dental personnel and its successful integration into the GNC's overall assessment program. However, rigorous dental support of the study centres is required for quality management

Associations between Prenatal Urinary Biomarkers of Phthalate Exposure and Preterm Birth: A Pooled Study of 16 US Cohorts

Importance: Phthalate exposure is widespread among pregnant women and may be a risk factor for preterm birth. Objective: To investigate the prospective association between urinary biomarkers of phthalates in pregnancy and preterm birth among individuals living in the US. Design, Setting, and Participants: Individual-level data were pooled from 16 preconception and pregnancy studies conducted in the US. Pregnant individuals who delivered between 1983 and 2018 and provided 1 or more urine samples during pregnancy were included. Exposures: Urinary phthalate metabolites were quantified as biomarkers of phthalate exposure. Concentrations of 11 phthalate metabolites were standardized for urine dilution and mean repeated measurements across pregnancy were calculated. Main Outcomes and Measures: Logistic regression models were used to examine the association between each phthalate metabolite with the odds of preterm birth, defined as less than 37 weeks of gestation at delivery (n = 539). Models pooled data using fixed effects and adjusted for maternal age, race and ethnicity, education, and prepregnancy body mass index. The association between the overall mixture of phthalate metabolites and preterm birth was also examined with logistic regression. G-computation, which requires certain assumptions to be considered causal, was used to estimate the association with hypothetical interventions to reduce the mixture concentrations on preterm birth. Results: The final analytic sample included 6045 participants (mean [SD] age, 29.1 [6.1] years). Overall, 802 individuals (13.3%) were Black, 2323 (38.4%) were Hispanic/Latina, 2576 (42.6%) were White, and 328 (5.4%) had other race and ethnicity (including American Indian/Alaskan Native, Native Hawaiian, >1 racial identity, or reported as other). Most phthalate metabolites were detected in more than 96% of participants. Higher odds of preterm birth, ranging from 12% to 16%, were observed in association with an interquartile range increase in urinary concentrations of mono-n-butyl phthalate (odds ratio [OR], 1.12 [95% CI, 0.98-1.27]), mono-isobutyl phthalate (OR, 1.16 [95% CI, 1.00-1.34]), mono(2-ethyl-5-carboxypentyl) phthalate (OR, 1.16 [95% CI, 1.00-1.34]), and mono(3-carboxypropyl) phthalate (OR, 1.14 [95% CI, 1.01-1.29]). Among approximately 90 preterm births per 1000 live births in this study population, hypothetical interventions to reduce the mixture of phthalate metabolite levels by 10%, 30%, and 50% were estimated to prevent 1.8 (95% CI, 0.5-3.1), 5.9 (95% CI, 1.7-9.9), and 11.1 (95% CI, 3.6-18.3) preterm births, respectively. Conclusions and Relevance: Results from this large US study population suggest that phthalate exposure during pregnancy may be a preventable risk factor for preterm delivery

Jet production in ep collisions at high Q(2) and determination of alpha(s)

The production of jets is studied in deep-inelastic e(+/-) p scattering at large negative four momentum transfer squared 150 LT Q(2) LT 15000 GeV2 using HERA data taken in 1999-2007, corresponding to an integrated luminosity of 395 pb(-1). Inclusive jet, 2-jet and 3-jet cross sections, normalised to the neutral current deep-inelastic scattering cross sections, are measured as functions of Q(2), jet transverse momentum and proton momentum fraction. The measurements are well described by perturbative QCD calculations at next-to-leading order corrected for hadronisation effects. The strong coupling as determined from these measurement

Repositioning of the global epicentre of non-optimal cholesterol

High blood cholesterol is typically considered a feature of wealthy western countries1,2. However, dietary and behavioural determinants of blood cholesterol are changing rapidly throughout the world3 and countries are using lipid-lowering medications at varying rates. These changes can have distinct effects on the levels of high-density lipoprotein (HDL) cholesterol and non-HDL cholesterol, which have different effects on human health4,5. However, the trends of HDL and non-HDL cholesterol levels over time have not been previously reported in a global analysis. Here we pooled 1,127 population-based studies that measured blood lipids in 102.6 million individuals aged 18 years and older to estimate trends from 1980 to 2018 in mean total, non-HDL and HDL cholesterol levels for 200 countries. Globally, there was little change in total or non-HDL cholesterol from 1980 to 2018. This was a net effect of increases in low- and middle-income countries, especially in east and southeast Asia, and decreases in high-income western countries, especially those in northwestern Europe, and in central and eastern Europe. As a result, countries with the highest level of non-HDL cholesterol—which is a marker of cardiovascular risk—changed from those in western Europe such as Belgium, Finland, Greenland, Iceland, Norway, Sweden, Switzerland and Malta in 1980 to those in Asia and the Pacific, such as Tokelau, Malaysia, The Philippines and Thailand. In 2017, high non-HDL cholesterol was responsible for an estimated 3.9 million (95% credible interval 3.7 million–4.2 million) worldwide deaths, half of which occurred in east, southeast and south Asia. The global repositioning of lipid-related risk, with non-optimal cholesterol shifting from a distinct feature of high-income countries in northwestern Europe, north America and Australasia to one that affects countries in east and southeast Asia and Oceania should motivate the use of population-based policies and personal interventions to improve nutrition and enhance access to treatment throughout the world.</p

Repositioning of the global epicentre of non-optimal cholesterol

High blood cholesterol is typically considered a feature of wealthy western countries1,2. However, dietary and behavioural determinants of blood cholesterol are changing rapidly throughout the world3 and countries are using lipid-lowering medications at varying rates. These changes can have distinct effects on the levels of high-density lipoprotein (HDL) cholesterol and non-HDL cholesterol, which have different effects on human health4,5. However, the trends of HDL and non-HDL cholesterol levels over time have not been previously reported in a global analysis. Here we pooled 1,127 population-based studies that measured blood lipids in 102.6 million individuals aged 18 years and older to estimate trends from 1980 to 2018 in mean total, non-HDL and HDL cholesterol levels for 200 countries. Globally, there was little change in total or non-HDL cholesterol from 1980 to 2018. This was a net effect of increases in low- and middle-income countries, especially in east and southeast Asia, and decreases in high-income western countries, especially those in northwestern Europe, and in central and eastern Europe. As a result, countries with the highest level of non-HDL cholesterol�which is a marker of cardiovascular risk�changed from those in western Europe such as Belgium, Finland, Greenland, Iceland, Norway, Sweden, Switzerland and Malta in 1980 to those in Asia and the Pacific, such as Tokelau, Malaysia, The Philippines and Thailand. In 2017, high non-HDL cholesterol was responsible for an estimated 3.9 million (95 credible interval 3.7 million�4.2 million) worldwide deaths, half of which occurred in east, southeast and south Asia. The global repositioning of lipid-related risk, with non-optimal cholesterol shifting from a distinct feature of high-income countries in northwestern Europe, north America and Australasia to one that affects countries in east and southeast Asia and Oceania should motivate the use of population-based policies and personal interventions to improve nutrition and enhance access to treatment throughout the world. © 2020, The Author(s), under exclusive licence to Springer Nature Limited

Rising rural body-mass index is the main driver of the global obesity epidemic in adults

Body-mass index (BMI) has increased steadily in most countries in parallel with a rise in the proportion of the population who live in cities 1,2 . This has led to a widely reported view that urbanization is one of the most important drivers of the global rise in obesity 3�6 . Here we use 2,009 population-based studies, with measurements of height and weight in more than 112 million adults, to report national, regional and global trends in mean BMI segregated by place of residence (a rural or urban area) from 1985 to 2017. We show that, contrary to the dominant paradigm, more than 55 of the global rise in mean BMI from 1985 to 2017�and more than 80 in some low- and middle-income regions�was due to increases in BMI in rural areas. This large contribution stems from the fact that, with the exception of women in sub-Saharan Africa, BMI is increasing at the same rate or faster in rural areas than in cities in low- and middle-income regions. These trends have in turn resulted in a closing�and in some countries reversal�of the gap in BMI between urban and rural areas in low- and middle-income countries, especially for women. In high-income and industrialized countries, we noted a persistently higher rural BMI, especially for women. There is an urgent need for an integrated approach to rural nutrition that enhances financial and physical access to healthy foods, to avoid replacing the rural undernutrition disadvantage in poor countries with a more general malnutrition disadvantage that entails excessive consumption of low-quality calories. © 2019, The Author(s)

Erratum: Pyrosequencing Evaluation of Widely Available Bisulfite Conversion Methods: Considerations for Application

<b><i>Introduction:</i></b> Bisulfite treatment of DNA introduces methylation-dependent sequence changes through selective chemical conversion of nonmethylated cytosine to uracil and serves as pretreatment step for the majority of DNA methylation analysis methods. <b><i>Methods:</i></b> We have evaluated the conversion performance of five of the most commonly used bisulfite treatment kits [MethylDetector (Active Motif), Epitect+ (Qiagen), Zymo Methylation, Zymo Gold and Zymo Lightning (all from Zymo Research)] by pyrosequencing four different regions with variable methylation levels, including: a repetitive element <i>(ALUSX)</i>, a gene with low levels of methylation <i>(IL6ST)</i>, an imprinted gene expected to be approximately 50% methylated <i>(IGF2)</i>, and a fully methylated gene <i>(ST3GAL2)</i>. In addition, we have studied the influence of duration (3 vs. 16 h) and type (fixed temperature vs. cycling program) of incubation protocol on the conversion efficiency of each evaluated kit. <b><i>Results:</i></b> All kits produced similar conversion rates of <i>ALUSX,</i><i>IGF2</i> and <i>ST3GAL2</i>, while the conversion of the low methylated <i>IL6ST</i> gene was variable between kits. The Zymo kits were highly consistent in their performance even when different protocols of incubation were applied, generating full conversion at the low methylated gene <i>IL6</i>; this was not true for the MethylDetector and Epitect+ kits. However, long-cycling incubation could produce similar conversion rates for the same locus in combination with Active Motif and Qiagen kits. <b><i>Conclusions:</i></b> The selection of a long-cycling protocol during conversion permits standardization of protocols, improving the reproducibility of methylation estimates across laboratories for gene-specific, genome-wide and bisulfite-based sequencing analyses