Detection of missed deaths in cancer registry data to reduce bias in long-term survival estimation.

Background: Population-based cancer survival estimates can provide insight into the real-world impacts of healthcare interventions and preventive services. However, estimation of survival rates obtained from population-based cancer registries can be biased due to missed incidence or incomplete vital status data. Long-term survival estimates in particular are prone to overestimation, since the proportion of deaths that are missed, for example through unregistered emigration, increases with follow-up time. This also applies to registry-based long-term prevalence estimates. The aim of this report is to introduce a method to detect missed deaths within cancer registry data such that long-term survival of cancer patients does not exceed survival in the general population. Methods: We analyzed data from 15 German epidemiologic cancer registries covering the years 1970-2016 and from Surveillance, Epidemiology, and End Results (SEER)-18 registries covering 1975-2015. The method is based on comparing survival times until exit (death or follow-up end) and ages at exit between deceased patients and surviving patients, stratified by diagnosis group, sex, age group and stage. Deceased patients with both follow-up time and age at exit in the highest percentile were regarded as outliers and used to fit a logistic regression. The regression was then used to classify each surviving patient as a survivor or a missed death. The procedure was repeated for lower percentile thresholds regarding deceased persons until long-term survival rates no longer exceeded the survival rates in the general population. Results: For the German cancer registry data, 0.9% of total deaths were classified as having been missed. Excluding these missed deaths reduced 20-year relative survival estimates for all cancers combined from 140% to 51%. For the whites in SEER data, classified missed deaths amounted to 0.02% of total deaths, resulting in 0.4 percent points lower 20-year relative survival rate for all cancers combined. Conclusion: The method described here classified a relatively small proportion of missed deaths yet reduced long-term survival estimates to more plausible levels. The effects of missed deaths should be considered when calculating long-term survival or prevalence estimates.

30 years after the fall of the Berlin Wall: Regional health differences in Germany.

Following the fall of the Berlin Wall in November 1989, considerable effort was made to bring the living conditions and levels of social participation in the former East German federal states into line with the former West German federal states. As a result, differences in health between the East and the West diminished significantly, in many cases as early as the 1990s, examples being life expectancy and cardiovascular mortality. In regard to health behaviour, the overall tendency has also clearly been one of convergence. Thus, only very small differences can be observed today, for example in the use of tobacco or in the prevalence of obesity. Yet the results also highlight the insufficiency of regarding the remaining differences as a simple comparison between East and West. Instead, the focus should shift towards smaller-scale approaches that take regional differences in living conditions into account.

A mixed linear model controlling for case underascertainment across multiple cancer registries estimated time trends in survival.

OBJECTIVES: Large temporal and geographical variation in survival rates estimated from epidemiological cancer registries coupled with heterogeneity in death certificate only (DCO) notifications makes it difficult to interpret trends in survival. The aim of our study is to introduce a method for estimating such trends while accounting for heterogeneity in DCO notifications in a cancer site-specific manner. STUDY DESIGN AND SETTING: We used the data of 4.0 million cancer cases notified in 14 German epidemiological cancer registries. Annual 5-year relative survival rates from 2002 through 2013 were estimated, and proportions of DCO notifications were recorded. "DCO-excluded" survival rates were regressed on DCO proportions and calendar years using a mixed linear model with cancer registry as a random effect. Based on this model, trends in survival rates were estimated for Germany at 0% DCO. RESULTS: For most cancer sites and age groups, we estimated significant positive trends in survival. Age-standardized survival for all cancers combined increased by 7.1% units for women and 10.8% units for men. CONCLUSION: The described method could be used to estimate trends in cancer survival based on the data from epidemiological cancer registries with differing DCO proportions and with changing DCO proportions over time.

Subsequent malignancies among long-term survivors of Hodgkin lymphoma and non-Hodgkin lymphoma: a pooled analysis of German cancer registry data (1990-2012).

The increased risk of subsequent primary malignancies (SPM) in survivors of adult-onset Hodgkin lymphoma (HL) and non-Hodgkin lymphoma (NHL) remains a challenging clinical problem worldwide. The German cancer registry database, pooled from 14 federal states, was used to calculate the standardized incidence ratio (SIR) and excess absolute risk (EAR) of SPM in 128 587 patients registered with first primary HL/NHL between 1990 and 2012. Conversely, SIRs were also calculated for a subsequent HL/NHL following other first cancers. The risk of developing SPM was significantly increased over twofold for HL survivors (SIR = 2·14, EAR = 51·87 cases/10 000 person-years) and 1·5-fold for NHL survivors (SIR = 1·48, EAR = 55·23) compared with the general German population. For solid cancers, SIRs were significantly elevated (1·6- and 1·4-fold; respectively) and were highest (threefold) in patients below 30 years of age upon initial diagnosis. Overall, SIRs were consistently elevated for lip/oral cavity, colon/rectum, lung, skin melanoma, breast, kidney and thyroid. Significantly increased SIRs for oesophagus, stomach, liver, pancreas, testis, prostate, and brain/central nervous system were observed following NHL only. For certain SPM, SIRs remained significantly elevated more than 10 years following HL/NHL diagnosis. Positive reciprocal associations were demonstrated between HL/NHL and several solid cancers mentioned above; for some, common aetiological mechanisms seem plausible.

Asthma management practices in adults--findings from the German Health Update (GEDA) 2010 and the German National Health Interview and Examination Survey (DEGS1) 2008-2011.

OBJECTIVES: In Germany, population-wide data on adherence to national asthma management guidelines are lacking, and performance measures (PM) for quality assurance in asthma care are systematically monitored for patients with German national asthma disease management program (DMP) enrollment only. We used national health survey data to assess variation in asthma care PM with respect to patient characteristics and care context, including DMP enrollment. METHODS: Among adults 18-79 years with self-reported physician-diagnosed asthma in the past 12 months identified from a recent German National Health Interview Survey (GEDA 2010: N = 1096) and the German National Health interview and Examination Survey 2008-2011 (DEGS1: N = 333), variation in asthma care PM was analyzed using logistic regression analysis. RESULTS: Overall, 38.4% (95% confidence interval: 32.5-44.6%) of adults with asthma were on current inhaled corticosteroid therapy. Regarding non-drug asthma management, low coverage was observed for inhaler technique monitoring (35.2%; 31.2-39.3%) and for provision of an asthma management plan (27.3%; 24.2-30.7%), particularly among those with low education. Specific PM were more complete among persons with than without asthma DMP enrollment (adjusted odds ratios ranging up to 10.19; 5.23-19.86), even if asthma patients were regularly followed in a different care context. CONCLUSIONS: Guideline adherence appears to be suboptimal, particularly with respect to PM related to patient counseling. Barriers to the translation of recommendations into practice need to be identified and continuous monitoring of asthma care PM at the population level needs to be established.

Differences of 25-hydroxyvitamin D3 concentrations in children and adults with neurofibromatosis type 1.

OBJECTIVES: Neurofibromatosis type 1 (NF1) is an autosomal dominant genetic disorder, frequently associated with reduced bone mineral density. Serum 25-hydroxyvitamin D3 concentrations in NF1 adults are lower than in healthy controls in autumn respectively winter and are inversely correlated with the number of dermal neurofibromas. We investigated 25-hydroxyvitamin D3 levels in children and adults with neurofibromatosis type 1 in winter and summer and compared them to healthy controls to get more pathogenic insights in vitamin D3 metabolism in NF1 patients. DESIGN AND METHODS: NF1 patients were clinically examined and serum 25-hydroxyvitamin D3 concentrations were measured in 58 NF1 adults and 46 children in winter as well as in summer and compared to sex-, age- and month-matched controls. RESULTS: 52 adults suffered from 10 to 5000 dermal neurofibromas, whereas none of the children presented neurofibromas. 25-Hydroxyvitamin D3 increased from winter to summer (mean: 21.0 to 46.5nmol/l) in NF1 adults. This increase was even larger (p=0.0001) than in healthy controls (mean: 50.5 to 60.5nmol/l). However, there were no differences of 25-hydroxyvitamin D3 concentrations in NF1 children and healthy controls both in winter and in summer. CONCLUSIONS: Only adults with NF1 showed lower 25-hydroxyvitamin D3 levels in winter and summer, which are unlikely due to impaired UV-dependent dermal synthesis, but rather might be caused by an accelerated catabolism.

Patterns of sensitization to inhalant and food allergens - findings from the German Health Interview and Examination Survey for Children and Adolescents.

BACKGROUND: To assess the prevalence of allergic sensitization and to analyze patterns of sensitization to common inhalant and food allergens in a nationwide representative sample of children and adolescents in Germany. METHODS: Data were collected from 2003 to 2006 within the KiGGS, the national Health Interview and Examination Survey covering a representative sample of 17,641 children and adolescents in Germany. Immunoglobulin E (IgE) antibodies to 20 specific allergens (11 inhalant and 9 food allergens) were quantitatively measured in a subsample of 12,988 KiGGS participants aged 3-17 years using the ImmunoCAP system. Serum concentrations ≥0.35 kU/l indicate sensitized participants. An exploratory factor analysis was performed in order to identify sensitization patterns. RESULTS: Sensitization to at least 1 of the 20 tested allergens was detected in 40.2% [95% confidence interval (CI) 39.0-41.4] of the participants. The highest sensitization prevalences were found for pollen from Timothy grass (22.7%; 21.5-23.9) and rye (21.2%; 20.0-22.4). Sensitization was more prevalent in boys than in girls and prevalence increased generally with increasing age. We identified seven sensitization groups, namely (in descending order of magnitude) 'Timothy grass/rye', 'house-dust mites', 'food/mugwort', 'birch/apple', 'animals', 'cow's milk/egg white' and 'moulds'. CONCLUSIONS: Allergic sensitization is common in German children and adolescents. The fact that sensitization potentially leads to clinically relevant allergic diseases stresses the public health relevance of this topic. Whether the grouping reflects the propensity for persons to be sensitized to multiple allergens within a group, or whether it is due to IgE cross-reactivity between different allergens of similar structure is still being discussed.

German health interview and examination survey for adults (DEGS) - design, objectives and implementation of the first data collection wave.

BACKGROUND: The German Health Interview and Examination Survey for Adults (DEGS) is part of the recently established national health monitoring conducted by the Robert Koch Institute. DEGS combines a nationally representative periodic health survey and a longitudinal study based on follow-up of survey participants. Funding is provided by the German Ministry of Health and supplemented for specific research topics from other sources. METHODS/DESIGN: The first DEGS wave of data collection (DEGS1) extended from November 2008 to December 2011. Overall, 8152 men and women participated. Of these, 3959 persons already participated in the German National Health Interview and Examination Survey 1998 (GNHIES98) at which time they were 18-79 years of age. Another 4193 persons 18-79 years of age were recruited for DEGS1 in 2008-2011 based on two-stage stratified random sampling from local population registries. Health data and context variables were collected using standardized computer assisted personal interviews, self-administered questionnaires, and standardized measurements and tests. In order to keep survey results representative for the population aged 18-79 years, results will be weighted by survey-specific weighting factors considering sampling and drop-out probabilities as well as deviations between the design-weighted net sample and German population statistics 2010. DISCUSSION: DEGS aims to establish a nationally representative data base on health of adults in Germany. This health data platform will be used for continuous health reporting and health care research. The results will help to support health policy planning and evaluation. Repeated cross-sectional surveys will permit analyses of time trends in morbidity, functional capacity levels, disability, and health risks and resources. Follow-up of study participants will provide the opportunity to study trajectories of health and disability. A special focus lies on chronic diseases including asthma, allergies, cardiovascular conditions, diabetes mellitus, and musculoskeletal diseases. Other core topics include vaccine-preventable diseases and immunization status, nutritional deficiencies, health in older age, and the association between health-related behavior and mental health.

A meta-analysis of QTL for diabetes-related traits in rodents.

Crossbreeding studies in rodents have identified numerous quantitative trait loci (QTL) that are linked to diabetes-related component traits. To identify genetic consensus regions implicated in insulin action and glucose homeostasis, we have performed a meta-analysis of genomewide linkage scans for diabetes-related traits. From a total of 43 published genomewide scans we assembled a nonredundant collection of 153 QTL for glucose levels, insulin levels, and glucose tolerance. Collectively, these studies include data from 48 different parental strains and >11,000 individual animals. The results of the studies were analyzed by the truncated product method (TPM). The analysis revealed significant evidence for linkage of glucose levels, insulin levels, and glucose tolerance to 27 different segments of the mouse genome. The most prominent consensus regions [localized to chromosomes 2, 4, 7, 9, 11, 13, and 19; logarithm of odds (LOD) scores 10.5-17.4] cover approximately 11% of the mouse genome and collectively contain the peak markers for 47 QTL. Approximately half of these genomic segments also show significant linkage to body weight and adiposity, indicating the presence of multiple obesity-dependent and -independent consensus regions for diabetes-related traits. At least 84 human genetic markers from genomewide scans and >80 candidate genes from human and rodent studies map into the mouse consensus regions for diabetes-related traits, indicating a substantial overlap between the species. Our results provide guidance for the identification of novel candidate genes and demonstrate the presence of numerous distinct consensus QTL regions with highly significant LOD scores that control glucose homeostasis. An interactive physical map of the QTL is available online at http://www.diabesitygenes.org.

Association of acyl-CoA-binding protein (ACBP) single nucleotide polymorphisms and type 2 diabetes in two German study populations.

The human acyl-CoA-binding protein (ACBP) is a potential candidate gene of type 2 diabetes (T2D), since it plays a central role in determining the intracellular concentration of activated fatty acids which contribute to insulin resistance. The aim of our study was to evaluate whether single nucleotide polymorphisms (SNPs) of the ACBP gene are associated with risk of T2D. Genotyping of eight SNPs (rs2084202, rs3731607, rs8192501, rs8192504, rs2244135, rs2276596, rs8192506, rs2289948) was performed in 192 incident T2D subjects and 384 matched controls of the European Prospective Investigation into Cancer and Nutrition-Potsdam cohort. A putative promoter SNP (rs2084202) of splice variant ACBP 1c showed decreased risk of T2D (odds ratio (OR) 0.63, 95% CI 0.41-0.96). The haplotype, that contained the mutant base of rs2084202 showed similar evidence for the association with disease risk as single SNP rs2084202. In a second population-based study, Cooperative Health Research in the Augsburg Region of 226 individuals with T2D and 863 control subjects a borderline significant association between rs2084202 and T2D (OR 0.72, 95% CI 0.51-1.01) was observed. In summary, we obtained evidence from two Caucasian study populations that the minor allele of ACBP rs2084202 might be associated with reduced risk of T2D.

A degradation-sensitive anionic trypsinogen (PRSS2) variant protects against chronic pancreatitis.

Chronic pancreatitis is a common inflammatory disease of the pancreas. Mutations in the genes encoding cationic trypsinogen (PRSS1) and the pancreatic secretory trypsin inhibitor (SPINK1) are associated with chronic pancreatitis. Because increased proteolytic activity owing to mutated PRSS1 enhances the risk for chronic pancreatitis, mutations in the gene encoding anionic trypsinogen (PRSS2) may also predispose to disease. Here we analyzed PRSS2 in individuals with chronic pancreatitis and controls and found, to our surprise, that a variant of codon 191 (G191R) is overrepresented in control subjects: G191R was present in 220/6,459 (3.4%) controls but in only 32/2,466 (1.3%) affected individuals (odds ratio 0.37; P = 1.1 x 10(-8)). Upon activation by enterokinase or trypsin, purified recombinant G191R protein showed a complete loss of trypsin activity owing to the introduction of a new tryptic cleavage site that renders the enzyme hypersensitive to autocatalytic proteolysis. In conclusion, the G191R variant of PRSS2 mitigates intrapancreatic trypsin activity and thereby protects against chronic pancreatitis.

Association of ENPP1 gene polymorphisms with hand osteoarthritis in a Chuvasha population.

Periarticular calcification is a common attendant symptom of generalized arterial calcification of infancy, a rare Mendelian disorder caused by mutations of the gene coding for ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1). This prompted us to perform a family-based association study to test the hypothesis that genetic variation at the ENPP1 locus is involved in the etiology of osteoarthritis of the hand. The study population comprised 126 nuclear families with 574 adult individuals living in small villages in the Chuvasha and Bashkirostan autonomies of the Russian Federation. The extent of osteoarthritis was determined by analyzing plain hand radiographs. The outcome of a principal component analysis of osteoarthritis scores of a total of 28 joints of both hands was used as a primary phenotype in this study. Maximum likelihood estimates of the variance component analysis revealed a substantial contribution of genetic factors to the overall trait variance of about 25% in this homogeneous population. Three short tandem repeat (STR) polymorphisms--one intragenic and two flanking markers--and four single-nucleotide polymorphisms were tested. The markers tagged the ENPP1 locus at nearly equal intervals. We used three different transmission disequilibrium tests and obtained highly significant association signals. Alleles of the upstream microsatellite marker as well as several single-nucleotide polymorphism haplotypes consistently revealed the association. Thus, our data highlights variability of ENPP1 as an important genetic factor in the pathogenesis of idiopathic osteoarthritis.

Association of ANKH gene polymorphisms with radiographic hand bone size and geometry in a Chuvasha population.

We performed a family-based association study to test the hypothesis that genetic variation at the human orthologue of the mouse progressive ankylosis gene (ANKH) is involved in determining bone size (BS) and bone geometry (BG). The study population comprised 126 nuclear families with 574 adult Chuvashian individuals living in small villages in the Russian Federation. Quantitative bone traits were determined by analyzing plain hand radiographs. Familial correlations for all studied traits revealed a high degree of heritability in this ethnically homogeneous population. Three simple tandem repeat (STR) polymorphisms, one intragenic and two flanking markers, as well as six single nucleotide polymorphisms (SNPs) were tested. The SNPs were detected by re-sequencing experiments and covered ANKH exons with their flanking splice sites and the promoter region. We used three different transmission disequilibrium tests (TDTs) and obtained multiple significant association signals for all investigated bone traits. Alleles of several markers located at different positions of the ANKH locus, including the promoter, consistently revealed the association. The bone traits tested are closely related to bone fragility suggesting a role for ANKH in osteoporosis.

Single nucleotide polymorphism map of five long-QT genes.

We screened a white population for single nucleotide polymorphisms (SNPs) in five long QT syndrome genes, namely, KCNQ1 (LQT1), HERG (LQT2), SCN5A (LQT3), KCNE1 (LQT5), and KCNE2 (LQT6). We found 35 SNPs, 10 of which have not been previously described. Ten SNPs were in KCNE1, six in HERG, eight in KCNQ1, four in KCNE2, and seven in SCN5A. Four SNPs were associated with QTc interval in our 141 subjects, one in KCNE1, one in KCNE2, and two in SCN5A. Two of these SNPs have not been described. We conclude that these five long QT syndrome genes contain common variants, some of which are associated with QTc interval in normal persons. We suggest that analysis of these SNPs in a much larger cohort would enable establishment of common haplotypes that are associated with QTc. These haplotypes could facilitate prediction of arrhythmia risk in the general population.