Childhood and adolescence factors and multiple sclerosis: results from the German National Cohort (NAKO).

BACKGROUND: Multiple Sclerosis (MS) represents the most common inflammatory neurological disease causing disability in early adulthood. Childhood and adolescence factors might be of relevance in the development of MS. We aimed to investigate the association between various factors (e.g., prematurity, breastfeeding, daycare attendance, weight history) and MS risk. METHODS: Data from the baseline assessment of the German National Cohort (NAKO) were used to calculate adjusted hazard ratios (HR) and 95% confidence intervals (CI) for the association between childhood and adolescence factors and risk of MS. Analyses stratified by sex were conducted. RESULTS: Among a total of 204,273 participants, 858 reported an MS diagnosis. Male sex was associated with a decreased MS risk (HR 0.48; 95% CI 0.41-0.56), while overweight (HR 2.03; 95% CI 1.41-2.94) and obesity (HR 1.89; 95% CI 1.02-3.48) at 18 years of age compared to normal weight were associated with increased MS risk. Having been breastfed for ≤ 4 months was associated with a decreased MS risk in men (HR 0.59; 95% CI 0.40-0.86) compared to no breastfeeding. No association with MS risk was observed for the remaining factors. CONCLUSIONS: Apart from overweight and obesity at the age of 18 years, we did not observe considerable associations with MS risk. The proportion of cases that can be explained by childhood and adolescence factors examined in this study was low. Further investigations of the association between the onset of overweight and obesity in childhood and adolescence and its interaction with physical activity and MS risk seem worthwhile.

Inverse association between apolipoprotein C-II and cardiovascular mortality: role of lipoprotein lipase activity modulation.

AIMS: Apolipoprotein C-II (ApoC-II) is thought to activate lipoprotein lipase (LPL) and is therefore a possible target for treating hypertriglyceridemia. Its relationship with cardiovascular risk has not been investigated in large-scale epidemiologic studies, particularly allowing for apolipoprotein C-III (ApoC-III), an LPL antagonist. Furthermore, the exact mechanism of ApoC-II-mediated LPL activation is unclear. METHODS AND RESULTS: ApoC-II was measured in 3141 LURIC participants of which 590 died from cardiovascular diseases during a median (inter-quartile range) follow-up of 9.9 (8.7-10.7) years. Apolipoprotein C-II-mediated activation of the glycosylphosphatidylinositol high-density lipoprotein binding protein 1 (GPIHBP1)-LPL complex was studied using enzymatic activity assays with fluorometric lipase and very low-density lipoprotein (VLDL) substrates. The mean ApoC-II concentration was 4.5 (2.4) mg/dL. The relationship of ApoC-II quintiles with cardiovascular mortality exhibited a trend toward an inverse J-shape, with the highest risk in the first (lowest) quintile and lowest risk in the middle quintile. Compared with the first quintile, all other quintiles were associated with decreased cardiovascular mortality after multivariate adjustments including ApoC-III as a covariate (all P < 0.05). In experiments using fluorometric substrate-based lipase assays, there was a bell-shaped relationship for the effect of ApoC-II on GPIHBP1-LPL activity when exogenous ApoC-II was added. In ApoC-II-containing VLDL substrate-based lipase assays, GPIHBP1-LPL enzymatic activity was almost completely blocked by a neutralizing anti-ApoC-II antibody. CONCLUSION: The present epidemiologic data suggest that increasing low circulating ApoC-II levels may reduce cardiovascular risk. This conclusion is supported by the observation that optimal ApoC-II concentrations are required for maximal GPIHBP1-LPL enzymatic activity.

Differences in risk profile associated with varicose veins and chronic venous insufficiency - results from the Bonn Vein Study 1.

Background: The aim of this publication is to demonstrate similarities and differences in the association of risk factors with the prevalence of different manifestations of chronic venous disease (CVD), like varicose veins (VV), venous oedema (C3) and severe chronic venous insufficiency (CVI) in the population-based cross-sectional Bonn Vein Study 1 (BVS). Patients and methods: In the BVS 1 between 13.11.2000 and 15.3.2002, 3.072 participants, 1350 men and 1722 women, from a simple random sample of the general population of the city of Bonn and two rural townships aged 18-79 years were included. The overall response proportion was 59%. All participants answered a standardized questionnaire including information about socio-economic data, lifestyle, physical activity, medical history, and quality of life. Venous investigations were performed clinically and by a standardized duplex examination by trained investigators. The CEAP classification in the version of 1996 was used to classify the findings. Logistic regression models were performed for the association of possible risk factors with VV, venous edema (C3) and severe CVI (C4-C6). The predictive risk (PR) describes the association of the diseases and the possible influencing factors. Results: VV, venous oedema (C3) and severe CVI (C4-C6) have common risk factors like higher age, number of pregnancies, family history of VV and overweight or obesity. Female gender is significantly associated with VV and C3 but not with severe CVI (C4-C6). High blood pressure and urban living are only associated with C3 and C4-C6 disease whereas prolonged sitting is associated with C3 and lower social class with C4-C6 exclusively. Discussion: In many epidemiological studies risk factors were associated with chronic venous disorders in general. Our data show that VV, venous edema and severe CVI may have different risk profiles. Venous edema is more often associated with arterial hypertension and sedentary lifestyle whereas lower social class seems to be a risk factor for severe CVI including venous ulcers. Conclusions: The differences in the association of risk factors to VV, venous edema and severe CVI should be considered if prevention and treatment of chronic venous diseases are planned. As examples, compression stockings could be proposed in sitting profession to prevent oedema, VV patients with risk factors like obesity might benefit from early treatment for VV and obesity. More longitudinal evaluation of risk factors is necessary to evaluate the true risk profile of CVD.

Time trends in survival and causes of death in multiple myeloma: a population-based study from Germany.

BACKGROUND: Steady evolution of therapies has improved prognosis of patients with multiple myeloma (MM) over the past two decades. Yet, knowledge about survival trends and causes of death in MM might play a crucial role in long-term management of this patient collective. Here, we investigate time trends in myeloma-specific survival at the population level over two decades and analyse causes of death in times of prolonged survival. METHODS: Age-standardised and age group-specific relative survival (RS) of MM patients aged < 80 years at diagnosis was estimated for consecutive time periods from 2000-2019 using data from the Cancer Registry of North Rhine-Westphalia in Germany. Conditional RS was estimated for patients who already survived one to five years post diagnosis. Causes of death in MM patients were analysed and compared to the general population using standardised mortality ratios (SMR). RESULTS: Three thousand three hundred thirty-six MM cases were included in the time trend analysis. Over two decades, age-standardised 5-year RS increased from 37 to 62%. Age-specific survival improved from 41% in period 2000-2004 to 69% in period 2015-2019 in the age group 15-69 years, and from 23 to 47% in the age group 70-79 years. Conditional 5-year RS of patients who survived five years after diagnosis slightly improved as compared to unconditional 5-year RS at diagnosis. MM patients are two times more likely to die from non-myeloma malignancies (SMR = 1.97, 95% CI 1.81-2.15) and from cardiovascular diseases (SMR = 2.01, 95% CI 1.86-2.18) than the general population. CONCLUSIONS: Prognosis of patients with MM has markedly improved since the year 2000 due to therapeutic advances. Nevertheless, late mortality remains a major concern. As survival improves, second primary malignancies and cardiovascular events deserve increased attention.

Testicular cancer mortality in Latin America and the Caribbean: trend analysis from 1997 to 2019.

BACKGROUND: In the last decades, an increasing incidence of testicular cancer has been observed in several countries worldwide. Although mortality rates have been variable in many countries, little information is available from Latin America and the Caribbean (LAC). Therefore, we examined mortality trends of testicular cancer in the last two decades. METHODS: Age-standardized mortality rates (ASMR) of testicular cancer per 100,000 men-years were estimated using the World Health Organization mortality database from 1997 to 2019. We examined the mortality trends and computed annual percent change (APC) for all ages and the following age groups, 15-29, 30-44, 15-44, and ≥ 45 years. RESULTS: Ten countries had mortality rates greater than 0.43 per 100,000 men, with the highest rates for Chile, Mexico, and Argentina. Significant increases in mortality rates were observed in Argentina, Brazil Colombia, and Mexico in all ages, and < 45 years, while Colombia, Ecuador, Mexico, and Peru reported significant downward trends in males aged ≥ 45 years. Only Chile showed significant decreases for all ages and age groups studied. CONCLUSION: Mortality by testicular cancer increased among LAC countries in males of all ages and across age groups. A reduction in mortality rates was observed only in Chilean males of all ages and in men ≥ 45 years in several countries. Strengthening of early detection among symptomatic males may decrease the mortality by this neoplasm.

Statistical inference and effect measures in abstracts of randomized controlled trials, 1975-2021. A systematic review.

OBJECTIVE: To examine the time trend of statistical inference, statistical reporting style of results, and effect measures from the abstracts of randomized controlled trials (RCTs). STUDY DESGIN AND SETTINGS: We downloaded 385,867 PubMed abstracts of RCTs from 1975 to 2021. We used text-mining to detect reporting of statistical inference (p-values, confidence intervals, significance terminology), statistical reporting style of results, and effect measures for binary outcomes, including time-to-event measures. We validated the text mining algorithms by random samples of abstracts. RESULTS: A total of 320 676 abstracts contained statistical inference. The percentage of abstracts including statistical inference increased from 65% (1975) to 87% (2006) and then decreased slightly. From 1975 to 1990, the sole reporting of language regarding statistical significance was predominant. Since 1990, reporting of p-values without confidence intervals has been the most common reporting style. Reporting of confidence intervals increased from 0.5% (1975) to 29% (2021). The two most common effect measures for binary outcomes were hazard ratios and odds ratios. Number needed to treat and number needed to harm are reported in less than 5% of abstracts with binary endpoints. CONCLUSIONS: Reporting of statistical inference in abstracts of RCTs has increased over time. Increasingly, p-values and confidence intervals are reported rather than just mentioning the presence of "statistical significance". The reporting of odds ratios comes with the liability that the untrained reader will interpret them as risk ratios, which is often not justified, especially in RCTs.

Estimates of excess mortality during the COVID-19 pandemic strongly depend on subjective methodological choices.

Excess mortality is often used to assess the health impact of the COVID-19 pandemic. It involves comparing the number of deaths observed during the pandemic with the number of deaths that would counterfactually have been expected in the absence of the pandemic. However, published data on excess mortality often vary even for the same country. The reason for these discrepancies is that the estimation of excess mortality involves a number of subjective methodological choices. The aim of this paper was to summarize these subjective choices. In several publications, excess mortality was overestimated because population aging was not adjusted for. Another important reason for different estimates of excess mortality is the choice of different pre-pandemic reference periods that are used to estimate the expected number of deaths (e.g., only 2019 or 2015-2019). Other reasons for divergent results include different choices of index periods (e.g., 2020 or 2020-2021), different modeling to determine expected mortality rates (e.g., averaging mortality rates from previous years or using linear trends), the issue of accounting for irregular risk factors such as heat waves and seasonal influenza, and differences in the quality of the data used. We suggest that future studies present the results not only for a single set of analytic choices, but also for sets with different analytic choices, so that the dependence of the results on these choices becomes explicit.

On the gap between objective and perceived risks of COVID-19.

A survey conducted by the German Socio-Economic Panel during the early phase of the SARS-CoV­2 pandemic in spring 2020 showed that the perceived risks of SARS-CoV­2 infection were a massive overestimation of the actual risks. A total of 5783 people (2.3% missing data) stated how likely they thought it was that SARS-CoV­2 would cause a life-threatening illness in them in the next 12 months. The average subjective probability was 26%. We consider how such an overestimation could have occurred and how a more realistic risk assessment could be achieved in the population in a future pandemic. We show that qualitative attributes of the pandemic, the reporting of the media, and psychological features may have contributed to the overestimation of SARS-CoV­2 risks. In its early stages, the SARS-CoV­2 pandemic had qualitative characteristics known to lead to an overestimation of risks: The risks associated with the pandemic were new, unfamiliar, perceived as poorly controllable, and were taken involuntarily. Phenomena known from cognitive psychology such as the availability and anchor heuristics can also explain the overestimation of pandemic risks. Characteristics of media coverage such as the focus on individual fates and the associated neglect of the denominator also contributed to the gap between perceived and objective risk. In a potential future pandemic, people need to be vigilant but not in a panic. Better risk communication-for example, with better prepared figures and graphically presented percentages while avoiding the denominator neglect-could help the population to perceive risks of future pandemics more realistically.

[Factors Influencing Results of Mortality Measurement in the Corona Pandemic: Analyses of Mortality in Germany in 2020]. / Einflussfaktoren auf Ergebnisse der Sterblichkeitsmessung in der Corona-Pandemie: Auswertungen zur Sterblichkeit in Deutschland im Jahr 2020.

INTRODUCTION: (Excess) mortality and years of life lost are important measures of health risks from the Corona pandemic. The aim of this paper was to identify methodological factors that affect the calculation of mortality and further to point out possible misinterpretations of years of life lost. METHODOLOGY: Standardized mortality ratios (SMRs) can be used to compare mortalities (e. g., an SMR of 1.015 means excess mortality of 1.5%, an SMR of 0.990 means that mortality is reduced by 1.0%). In this study, SMRs as a measure of association for mortality in Germany were calculated for 2020 using different methods. In particular, the influence of different data sources and reference periods was examined. Furthermore, its influence on the calculated mortality was also examined to take into account increasing life expectancy. In addition, published results on years of life lost were critically analyzed. RESULTS: Using January 2022 data from the Federal Statistical Office on mortality for 5-year age groups resulted in higher SMR values than using preliminary data from February 2021 with 20-year age groups (SMR=0.997, 95% confidence interval (CI): 0.995-0.999 versus SMR=0.976 (95% CI: 0.974-0.978)). The choice of the reference period had a large impact on calculated mortality (for men, SMR=1.024 (95% CI: 1.022-1.027) with 2019 as the reference year versus SMR=0.998 (95% CI: 0.996-1.001) with 2016 to 2019 as the reference period). Analyses in which declining mortality in 2016 to 2019 was carried forward into 2020 when calculating expected deaths resulted in significantly higher SMR values (for men SMR=1.024 (95% CI: 1.021-1.026) with, and SMR=0.998 (95% CI: 0.996-1.001) without carrying forward declining mortality). Figures for pandemic-related years of life lost per person who died from COVID-19 should be interpreted with caution: Calculation from remaining life reported in mortality tables can lead to misleading results. CONCLUSION: When calculating mortality and years of life lost during the pandemic, a number of methodological assumptions must be made that have a significant impact on the results and must be considered when interpreting the results.

[Regional Differences in Thyroid Function Parameters: A Comparison of European Cohort Studies]. / Regionale Unterschiede von Schilddrüsenfunktionsparametern: ein Vergleich europäischer Kohortenstudien.

AIM OF THE STUDY: The aim of the project was to investigate regional differences in thyroid stimulating hormone (TSH), and free thyroxine (fT4) concentrations and iodine status in comparable German and European cohort studies. METHODS: Sex- and age-stratified TSH, fT4, and urine iodine concentrations of thyroid-healthy participants (age group 45-75 years) of the HNR (Heinz Nixdorf Recall) Study in the Ruhr region of Germany, the southern German KORA (Cooperative Health Research in the Augsburg Region) and northeastern German SHIP (Study of Health in Pomerania) studies, as well as the Norwegian HUNT (Nord-Trøndelag Health) study (age group 40-79 years), the English EPIC (European Prospective Investigation of Cancer)-Norfolk study, and the Dutch Rotterdam study were compared. The TSH reference range for the HNR study population was calculated and compared to the KORA and SHIP studies. RESULTS: Regional differences showed a stronger influence on TSH and fT4 concentrations than sex and age of the subjects in the 45- to 75-year age group. The estimated difference in medians, as measured by the HNR study, was lowest in the SHIP study, -0.47 (95% CI: -0.53; -0.41) for men and -0.41 (-0.53; -0.41) for women. The Rotterdam study had the highest difference in medians for both men and women (men: 0.56 with 0.44; 0.68 and women: 0.62 with 0.46; 0.78). The lowest median TSH concentrations, across all age categories considered, were seen in the German cohorts. CONCLUSIONS: Comparison of thyroid function parameters and iodine in elderly subjects between six comparable cohort studies from Germany and Europe showed a significant influence of region, which exceeded the sex and age dependence of the parameters.

Distance-Metric Learning for Personalized Survival Analysis.

Personalized time-to-event or survival prediction with right-censored outcomes is a pervasive challenge in healthcare research. Although various supervised machine learning methods, such as random survival forests or neural networks, have been adapted to handle such outcomes effectively, they do not provide explanations for their predictions, lacking interpretability. In this paper, an alternative method for survival prediction by weighted nearest neighbors is proposed. Fitting this model to data entails optimizing the weights by learning a metric. An individual prediction of this method can be explained by providing the user with the most influential data points for this prediction, i.e., the closest data points and their weights. The strengths and weaknesses in terms of predictive performance are highlighted on simulated data and an application of the method on two different real-world datasets of breast cancer patients shows its competitiveness with established methods.

Lifetime Exposure to Welding Fumes and Risk of Some Rare Cancers.

We investigated the association between exposure to welding fumes and the risk of biliary tract, male breast, bone, and thymus cancer, as well as cancer of the small intestine, eye melanoma, and mycosis fungoides, among men in a European, multicenter case-control study. From 1995-1997, 644 cases and 1,959 control subjects from 7 countries were studied with respect to information on welding and potential confounders. We linked the welding histories of the participants with a measurement-based exposure matrix to calculate lifetime exposure to welding fumes. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using logistic regression models, conditional on country and 5-year age groups, and adjusted for education and relevant confounders. Regular welding was associated with an increased risk of cancer of the small intestine (OR = 2.30, 95% CI: 1.17, 4.50). Lifetime exposure to welding fumes above the median of exposed controls was associated with an increased risk of cancer of the small intestine (OR = 2.00, 95% CI: 1.07, 3.72) and male breast (OR = 2.07, 95% CI: 1.14, 3.77), and some elevation in risk was apparent for bone cancer (OR = 1.92, 95% CI: 0.85, 4.34) with increasing lifetime exposure to welding fumes. Welding fumes could contribute to an increased risk of some rare cancers.

A twenty-first century perspective on concepts of modern epidemiology in Ignaz Philipp Semmelweis' work on puerperal sepsis.

We aimed to review Semmelweis's complete work on puerperal sepsis mortality in maternity wards in relation to exposure to cadavers and chlorine handwashing and other factors from the perspective of modern epidemiological methods. We reviewed Semmelweis' complete work and data as published by von Györy 1905 according to current standards. We paid particular attention to Semmelweis's definition of mortality in and of itself, to concepts of modern epidemiology that were already recognizable in Semmelweis's work, and to bias sources. We did several quantitative bias analyses to address selection bias and information bias from outcome measurement error. Semmelweis addressed biases that have become known to modern epidemiology, such as confounding, selection bias and bias from outcome misclassification. Our bias analysis shows that differential loss to follow-up is an unlikely explanation for his results. Bias due to outcome misclassification would only be relevant if misclassification differed between time periods. Confounding by health status was likely but could not be quantitatively addressed. Semmelweis was aware that cause-specific mortality is a function of incidence and prognosis. He reasoned in potential outcome terms to estimate the reduced number of deaths from an intervention. He advanced a hypothesis of clinic overcrowding as a risk factor for puerperal sepsis mortality that turns out to be wrong. Semmelweis' data provide a great pool for illustrating the logic of scientific discovery by use of the numerical method. The explanatory power of his work was strong and Semmelweis was able to refute several previous causal explanations.

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.

External validation of six clinical models for prediction of chronic kidney disease in a German population.

BACKGROUND: Chronic kidney disease (CKD) is responsible for large personal health and societal burdens. Screening populations at higher risk for CKD is effective to initiate earlier treatment and decelerate disease progress. We externally validated clinical prediction models for unknown CKD that might be used in population screening. METHODS: We validated six risk models for prediction of CKD using only non-invasive parameters. Validation data came from 4,185 participants of the German Heinz-Nixdorf-Recall study (HNR), drawn in 2000 from a general population aged 45-75 years. We estimated discrimination and calibration using the full model information, and calculated the diagnostic properties applying the published scoring algorithms of the models using various thresholds for the sum of scores. RESULTS: The risk models used four to nine parameters. Age and hypertension were included in all models. Five out of six c-values ranged from 0.71 to 0.73, indicating fair discrimination. Positive predictive values ranged from 15 to 19%, negative predictive values were > 93% using score thresholds that resulted in values for sensitivity and specificity above 60%. CONCLUSIONS: Most of the selected CKD prediction models show fair discrimination in a German general population. The estimated diagnostic properties indicate that the models are suitable for identifying persons at higher risk for unknown CKD without invasive procedures.

One-year follow-up healthcare costs of patients diagnosed with skin cancer in Germany: a claims data analysis.

BACKGROUND: Routine skin cancer screening (SCS) is covered by the German statutory health insurance (SHI) since 2008. The objective of this study was to compare direct healthcare costs between patients in whom skin cancer was detected by routine SCS and patients in whom skin cancer was not detected by routine SCS. METHODS: A retrospective observational study of administrative claims data from a large German SHI was performed. Patients with a diagnosis of malignant melanoma (MM) or non-melanoma skin cancer (NMSC) diagnosed in 2014 or 2015 were included. Costs were obtained for one year before and one year after diagnosis and analyzed in a difference-in-differences approach using regression models. Frequency matching was applied and risk adjustment was performed. Additional analyses were conducted, separately for specific age groups, excluding persons who died during the observation period and without taking costs for screening into consideration. RESULTS: A total of 131,801 patients were included, of whom 13,633 (10.3%) had a diagnosis of MM and 118,168 (89.7%) had a diagnosis of NMSC. The description of total costs (without risk adjustment) shows lower mean total costs among patients whose skin cancer was detected via routine SCS compared to patients in whom skin cancer was not detected by routine SCS (MM: €5,326 (95% confidence interval (CI) €5,073; €5,579) vs. €9,038 (95% CI €8,629; €9,448); NMSC: €4,660 (95% CI €4,573; €4,745) vs. €5,890 (95% CI €5,813; €5,967)). Results of the regression analysis show cost savings of 18.8% (95% CI -23.1; -8.4) through routine SCS for patients with a diagnosis of MM. These cost savings in MM patients were more pronounced in patients younger than 65 years of age. For patients with a diagnosis of NMSC, the analysis yields a non-substantial increase in costs (2.5% (95% CI -0.1; 5.2)). CONCLUSION: Cost savings were detected for persons with an MM diagnosed by routine SCS. However, the study could not detect lower costs due to routine SCS in the large fraction of persons with a diagnosis of NMSC. These results offer important insights into the cost structure of the routine SCS and provide opportunities for refinements.

Associations between haemoglobin A1c and mortality rate in the KORA S4 and the Heinz Nixdorf Recall population-based cohort studies.

BACKGROUND: There is limited knowledge about mortality risk in persons with increased haemoglobin A1c (HbA1c ) levels below the diabetes threshold. Moreover, little is known about how associations between increased HbA1c and mortality depend on the length of follow-up. Therefore, we studied associations between HbA1c and mortality over long-term follow-up in persons with and without known diabetes. METHODS: We used data from two German population-based cohort studies: KORA S4 Study (Southern Germany, n = 1458, baseline visits in 1999 to 2001, baseline age 55 to 74 years, mortality follow-up 16.8 years) and Heinz Nixdorf Recall (HNR) Study (Ruhr area, n = 4613, baseline visits in 2000 to 2003, baseline age 45 to 75 years, mortality follow-up 17.8 years). Adjusted log-linear models were fitted to estimate relative risks (RRs) with 95% confidence intervals (CI). RESULTS: In both cohorts, participants with HbA1c 39 to 41 mmol/mol (5.7%-5.9%) and HbA1c 42 to 46 mmol/mol (6.0% to 6.4%) did not have a larger overall mortality risk than participants with HbA1c < 39 mmol/mol (5.7%): the corresponding adjusted RRs were 1.00 (95% CI: 0.83-1.21) and 1.01 (0.80-1.27) in KORA and 0.99 (0.82-1.21) and 0.83 (0.65-1.07) in the HNR Study. For the pooled cohorts, the RR for HbA1c 39 to 46 mmol/mol (5.7%-6.4%) was 0.96 (0.85-1.07). Associations between newly detected diabetes (HbA1c ≥ 6.5%) and mortality were weak after 4 and 8 years of follow-up, but were stronger after 12 years of follow-up, whereas associations between previously known diabetes (baseline) and mortality decreased. CONCLUSIONS: HbA1c -defined pre-diabetes is not associated with overall mortality. For newly detected and previously known diabetes, mortality risks vary with length of follow-up.

Prospective comparison of the diagnostic accuracy of 18F-FDG PET/MRI, MRI, CT, and bone scintigraphy for the detection of bone metastases in the initial staging of primary breast cancer patients.

OBJECTIVES: To compare the diagnostic performance of [18F]FDG PET/MRI, MRI, CT, and bone scintigraphy for the detection of bone metastases in the initial staging of primary breast cancer patients. MATERIAL AND METHODS: A cohort of 154 therapy-naive patients with newly diagnosed, histopathologically proven breast cancer was enrolled in this study prospectively. All patients underwent a whole-body [18F]FDG PET/MRI, computed tomography (CT) scan, and a bone scintigraphy prior to therapy. All datasets were evaluated regarding the presence of bone metastases. McNemar χ2 test was performed to compare sensitivity and specificity between the modalities. RESULTS: Forty-one bone metastases were present in 7/154 patients (4.5%). Both [18F]FDG PET/MRI and MRI alone were able to detect all of the patients with histopathologically proven bone metastases (sensitivity 100%; specificity 100%) and did not miss any of the 41 malignant lesions (sensitivity 100%). CT detected 5/7 patients (sensitivity 71.4%; specificity 98.6%) and 23/41 lesions (sensitivity 56.1%). Bone scintigraphy detected only 2/7 patients (sensitivity 28.6%) and 15/41 lesions (sensitivity 36.6%). Furthermore, CT and scintigraphy led to false-positive findings of bone metastases in 2 patients and in 1 patient, respectively. The sensitivity of PET/MRI and MRI alone was significantly better compared with CT (p < 0.01, difference 43.9%) and bone scintigraphy (p < 0.01, difference 63.4%). CONCLUSION: [18F]FDG PET/MRI and MRI are significantly better than CT or bone scintigraphy for the detection of bone metastases in patients with newly diagnosed breast cancer. Both CT and bone scintigraphy show a substantially limited sensitivity in detection of bone metastases. KEY POINTS: • [18F]FDG PET/MRI and MRI alone are significantly superior to CT and bone scintigraphy for the detection of bone metastases in patients with newly diagnosed breast cancer. • Radiation-free whole-body MRI might serve as modality of choice in detection of bone metastases in breast cancer patients.

Statistical inference in abstracts of three influential clinical pharmacology journals analyzed using a text-mining algorithm.

AIM: To describe the trend in the prevalence of statistical inference in three influential clinical pharmacology journals METHODS: We applied a computer-based algorithm to abstracts of three clinical pharmacology journals published in 1976 to 2016 to identify statistical inference and its subtypes. Furthermore, we manually reviewed a random sample of 300 articles to access algorithm's performance in finding statistical inference in abstracts and as a screening tool for presence and absence of statistical inference in full text. RESULT: The algorithm identified 59% (13,375/22,516 [mid p 95% CI, 59%-60%]) article abstracts with statistical inference. The percentage of abstracts with statistical inference was similar in 1976 and 2016, 48% (179/377 [mid p 95%CI, 42%-52%]) versus 49% (386/791 [mid p 95%CI, 45%-52%]). Statistical reporting pattern varied among journals. Among abstracts containing any statistical inference in the publications from 1976 to 2016 null-hypothesis significance testing was the most prevalent reported statistical inference. The algorithm had high sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) for finding statistical inferences in abstract. While PPV for predicting the statistical inference in full text (including abstract, text, tables and figures) was high, NPV was low. CONCLUSION: Despite journal's editorials and statistical associations' guidelines, most authors focused on testing rather than estimation. In future, a better statistical reporting might be ensured by improving the statistical knowledge of authors and an addition of statistical guides to journals' instruction to authors to the extent that editors would like their statistical inference preferences to be incorporated into submitted manuscripts.

Decline of coronary heart disease mortality is strongly effected by changing patterns of underlying causes of death: an analysis of mortality data from 27 countries of the WHO European region 2000 and 2013.

Mortality rates for coronary heart disease (CHD) experience a longstanding decline, attributed to progress in prevention, diagnostics and therapy. However, CHD mortality rates vary between countries. To estimate whether national patterns of causes of death impact CHD mortality, data from the WHO "European detailed mortality database" for 2000 and 2013 for populations aged ≥ 80 years was analyzed. We extracted mortality rates for total mortality, cardiovascular diseases, neoplasms, dementia and ill-defined causes. We calculated proportions of selected causes of death among all deaths, and proportions of selected cardiovascular causes among cardiovascular deaths. CHD mortality rates were recalculated after re-coding ill-defined causes of death. Association between CHD mortality rates and proportions of CHD deaths was estimated by population-weighted linear regression. National patterns of causes of death were divers. In 2000, CHD was assigned as cause of death in 13-53% of all cardiovascular deaths. Until 2013, this proportion changed between - 65% (Czech Republic) and + 57% (Georgia). Dementia was increasingly assigned as underlying cause of death in Western Europe, but rarely in eastern European countries. Ill-defined causes accounted for between < 1% and 53% of all cardiovascular deaths. CHD mortality rates were closely linked to a countries' proportion of cardiovascular deaths assigned to CHD (R2 = 0.95 for 2000 and 0.99 for 2013). We show that CHD mortality is considerably influenced by national particularities in certifying death. Changes in CHD mortality rates reflect changes in certifying competing underlying causes of death. This must be accounted for when discussing reasons for the CHD mortality decline.