Clinical epidemiology of vaccines and vaccine-preventable diseases using administrative healthcare data

For centuries, infectious diseases have been among the top 10 leading causes of death. In 2015, they accounted for about 11% of 56.4 million deaths worldwide indicating a global public health relevance. Vaccines provide an opportunity to eliminate or even eradicate infectious diseases. In order to maximize the benefit of vaccines while minimizing their risks, it is important to investigate infectious disease etiology as well as to continuously monitor and evaluate direct vaccination effects as well as indirect vaccination effects through herd immunity. Since vaccines are usually administered to healthy people to prevent infectious diseases, the monitoring of the safety of vaccines is of high importance. For their evaluation, there is usually no trade-off between risk of disease and risk of its treatment as is usually the case for the treatment of severe diseases. Vaccine safety is also essential for the acceptance of vaccines in the population and thus for high vaccine uptake to enable herd immunity. Epidemiological observational studies are a powerful tool to investigate the burden of vaccine-preventable diseases, direct and indirect vaccination effects as well as the safety of vaccines in a real-world setting, meaning they provide important data as they includea often in contrast to randomized controlled trialsa older or immunocompromised people as well as children or pregnant women, which are most often the target population groups for vaccinations. Administrative data are a valuable data source for epidemiological observational studies and are increasingly used for studies on vaccines and vaccine-preventable diseases. However, a comprehensive knowledge of the healthcare system itself, including reimbursement policies, but also of the data source and the containing information depth is required. This thesis investigates different aspects of vaccines and vaccine-preventable diseases. Thus, in a first study, the burden of the vaccine-preventable disease of herpes zoster (HZ) and its complications is investigated and in a separate study, the risk of stroke complication after HZ infection. Vaccine uptake of the human papillomavirus (HPV) vaccine at the population level as well as its indirect impact after vaccine recommendation is assessed. Furthermore, this thesis discusses the nested case-control design with respect to its potential use for direct effectiveness and safety studies of vaccines. Relevant methodological challenges when using different observational study designs based on administrative healthcare data as well as methods to control confounding or to reduce bias are elucidated and discussed. Finally, this thesis gives outlook on potential challenges of future studies on vaccines and vaccine-preventable diseases, especially with regard to newly developed therapeutic vaccines for chronic diseases

Toward a Dimensional Assessment of Externalizing Disorders in Children: Reliability and Validity of a Semi-Structured Parent Interview

Objective This study assesses the reliability and validity of the DSM-5-based, semi-structured Clinical Parent Interview for Externalizing Disorders in Children and Adolescents (ILF-EXTERNAL). Method Participant data were drawn from the ongoing ESCAschool intervention study. The ILF-EXTERNAL was evaluated in a clinical sample of 474 children and adolescents (aged 6-12 years, 92 females) with symptoms of attention-deficit/hyperactivity disorder (ADHD). To obtain interrater reliability, the one-way random-effects, absolute agreement models of the intraclass correlation (ICC) for single ICC(1,1) and average measurements ICC(1,3) were computed between the interviewers and two independent raters for 45 randomly selected interviews involving ten interviewers. Overall agreement on DSM-5 diagnoses was assessed using Fleiss' kappa. Further analyses evaluated internal consistencies, item-total correlations as well as correlations between symptom severity and the degree of functional impairment. Additionally, parents completed the German version of the Child Behavior Checklist (CBCL) and two DSM-5-based parent questionnaires for the assessment of ADHD symptoms and symptoms of disruptive behavior disorders (FBB-ADHS; FBB-SSV), which were used to evaluate convergent and divergent validity. Results ICC coefficients demonstrated very good to excellent interrater reliability on the item and scale level of the ILF-EXTERNAL [scale level: ICC(1,1) = 0.83-0.95; ICC(1,3) = 0.94-0.98]. Overall kappa agreement on DSM-5 diagnoses was substantial to almost perfect for most disorders (0.38 ≤ κ ≤ 0.94). With some exceptions, internal consistencies (0.60 ≤ α ≤ 0.86) and item-total correlations (0.21 ≤ r$_{it}$ ≤ 0.71) were generally satisfactory to good. Furthermore, higher symptom severity was associated with a higher degree of functional impairment. The evaluation of convergent validity revealed positive results regarding clinical judgment and parent ratings (FBB-ADHS; FBB-SSV). Correlations between the ILF-EXTERNAL scales and the CBCL Externalizing Problems were moderate to high. Finally, the ILF-EXTERNAL scales were significantly more strongly associated with the CBCL Externalizing Problems than with the Internalizing Problems, indicating divergent validity. Conclusion In clinically referred, school-age children, the ILF-EXTERNAL demonstrates sound psychometric properties. The ILF-EXTERNAL is a promising clinical interview and contributes to high-quality diagnostics of externalizing disorders in children and adolescents

Polygenic Risk Scores for Prediction of Breast Cancer and Breast Cancer Subtypes

Stratification of women according to their risk of breast cancer based on polygenic risk scores (PRSs) could improve screening and prevention strategies. Our aim was to develop PRSs, optimized for prediction of estrogen receptor (ER)-specific disease, from the largest available genome-wide association dataset and to empirically validate the PRSs in prospective studies. The development dataset comprised 94,075 case subjects and 75,017 control subjects of European ancestry from 69 studies, divided into training and validation sets. Samples were genotyped using genome-wide arrays, and single-nucleotide polymorphisms (SNPs) were selected by stepwise regression or lasso penalized regression. The best performing PRSs were validated in an independent test set comprising 11,428 case subjects and 18,323 control subjects from 10 prospective studies and 190,040 women from UK Biobank (3,215 incident breast cancers). For the best PRSs (313 SNPs), the odds ratio for overall disease per 1 standard deviation in ten prospective studies was 1.61 (95%CI: 1.57-1.65) with area under receiver-operator curve (AUC) = 0.630 (95%CI: 0.628-0.651). The lifetime risk of overall breast cancer in the top centile of the PRSs was 32.6%. Compared with women in the middle quintile, those in the highest 1% of risk had 4.37- and 2.78-fold risks, and those in the lowest 1% of risk had 0.16- and 0.27-fold risks, of developing ER-positive and ER-negative disease, respectively. Goodness-of-fit tests indicated that this PRS was well calibrated and predicts disease risk accurately in the tails of the distribution. This PRS is a powerful and reliable predictor of breast cancer risk that may improve breast cancer prevention programs.NovartisEli Lilly and CompanyAstraZenecaAbbViePfizer UKCelgeneEisaiGenentechMerck Sharp and DohmeRocheCancer Research UKGovernment of CanadaArray BioPharmaGenome CanadaNational Institutes of HealthEuropean CommissionMinistère de l'Économie, de l’Innovation et des Exportations du QuébecSeventh Framework ProgrammeCanadian Institutes of Health Researc

Transcriptome-wide association study of breast cancer risk by estrogen-receptor status

Previous transcriptome-wide association studies (TWAS) have identified breast cancer risk genes by integrating data from expression quantitative loci and genome-wide association studies (GWAS), but analyses of breast cancer subtype-specific associations have been limited. In this study, we conducted a TWAS using gene expression data from GTEx and summary statistics from the hitherto largest GWAS meta-analysis conducted for breast cancer overall, and by estrogen receptor subtypes (ER+ and ER-). We further compared associations with ER+ and ER- subtypes, using a case-only TWAS approach. We also conducted multigene conditional analyses in regions with multiple TWAS associations. Two genes, STXBP4 and HIST2H2BA, were specifically associated with ER+ but not with ER- breast cancer. We further identified 30 TWAS-significant genes associated with overall breast cancer risk, including four that were not identified in previous studies. Conditional analyses identified single independent breast-cancer gene in three of six regions harboring multiple TWAS-significant genes. Our study provides new information on breast cancer genetics and biology, particularly about genomic differences between ER+ and ER- breast cancer.Peer reviewe

Genome-wide association study of germline variants and breast cancer-specific mortality

BACKGROUND: We examined the associations between germline variants and breast cancer mortality using a large meta-analysis of women of European ancestry. METHODS: Meta-analyses included summary estimates based on Cox models of twelve datasets using ~10

Klinische Epidemiologie von Impfungen und impfpräventablen Erkrankungen auf Basis von Routinedaten der gesetzlichen Krankenversicherung

For centuries, infectious diseases have been among the top 10 leading causes of death. In 2015, they accounted for about 11% of 56.4 million deaths worldwide indicating a global public health relevance. Vaccines provide an opportunity to eliminate or even eradicate infectious diseases. In order to maximize the benefit of vaccines while minimizing their risks, it is important to investigate infectious disease etiology as well as to continuously monitor and evaluate direct vaccination effects as well as indirect vaccination effects through herd immunity. Since vaccines are usually administered to healthy people to prevent infectious diseases, the monitoring of the safety of vaccines is of high importance. For their evaluation, there is usually no trade-off between risk of disease and risk of its treatment as is usually the case for the treatment of severe diseases. Vaccine safety is also essential for the acceptance of vaccines in the population and thus for high vaccine uptake to enable herd immunity. Epidemiological observational studies are a powerful tool to investigate the burden of vaccine-preventable diseases, direct and indirect vaccination effects as well as the safety of vaccines in a real-world setting, meaning they provide important data as they includea often in contrast to randomized controlled trialsa older or immunocompromised people as well as children or pregnant women, which are most often the target population groups for vaccinations. Administrative data are a valuable data source for epidemiological observational studies and are increasingly used for studies on vaccines and vaccine-preventable diseases. However, a comprehensive knowledge of the healthcare system itself, including reimbursement policies, but also of the data source and the containing information depth is required. This thesis investigates different aspects of vaccines and vaccine-preventable diseases. Thus, in a first study, the burden of the vaccine-preventable disease of herpes zoster (HZ) and its complications is investigated and in a separate study, the risk of stroke complication after HZ infection. Vaccine uptake of the human papillomavirus (HPV) vaccine at the population level as well as its indirect impact after vaccine recommendation is assessed. Furthermore, this thesis discusses the nested case-control design with respect to its potential use for direct effectiveness and safety studies of vaccines. Relevant methodological challenges when using different observational study designs based on administrative healthcare data as well as methods to control confounding or to reduce bias are elucidated and discussed. Finally, this thesis gives outlook on potential challenges of future studies on vaccines and vaccine-preventable diseases, especially with regard to newly developed therapeutic vaccines for chronic diseases

Non-Steroidal Anti-Inflammatory Drug Use and the Risk of Acute Myocardial Infarction in the General German Population: A Nested Case–Control Study

INTRODUCTION: Use of non-steroidal anti-inflammatory drugs (NSAIDs) has been associated with an increased relative risk of acute myocardial infarction (AMI), but the label warnings refer particularly to patients with cardiovascular risk factors. The magnitude of relative AMI risk for patients with and without cardiovascular risk factors varies between studies depending on the drugs and doses studied. OBJECTIVES: The aim of our study was to estimate population-based relative AMI risks for individual and widely used NSAIDs, for a cumulative amount of NSAID use, and for patients with and without a prior history of cardiovascular risk factors. METHODS: Based on data from the German Pharmacoepidemiological Research Database (GePaRD) of about 17 million insurance members from four statutory health insurance providers, for the years 2004–2009, a nested case–control study was conducted within a cohort of 3,476,931 new NSAID users classified into current, recent, or past users. Up to 100 controls were matched to each case by age, sex, and length of follow-up using risk set sampling. Multivariable conditional logistic regression was applied to estimate odds ratios (ORs) and 95% confidence intervals (CIs). Duration of NSAID use was calculated by the cumulative amount of dispensed defined daily doses (DDDs), and stratified analyses were conducted for potential effect modifiers. RESULTS: Overall, 17,236 AMI cases were matched to 1,714,006 controls. Elevated relative AMI risks were seen for current users of fixed combinations of diclofenac with misoprostol (OR 1.76, 95% CI 1.26–2.45), indometacin (1.69, 1.22–2.35), ibuprofen (1.54, 1.43–1.65), etoricoxib (1.52, 1.24–1.87), and diclofenac (1.43, 1.34–1.52) compared with past use. A low cumulative NSAID amount was associated with a higher relative AMI risk for ibuprofen, diclofenac, and indometacin. The relative risk associated with current use of diclofenac, fixed combinations of diclofenac with misoprostol, etoricoxib, and ibuprofen was highest in the younger age group (<60 years) and similar for patients with or without major cardiovascular risk factors. CONCLUSION: Relative AMI risk estimates differed among the 15 investigated individual NSAIDs. Diclofenac and ibuprofen, the most frequently used NSAIDs, were associated with a 40–50% increased relative risk of AMI, even for low cumulative NSAID amounts. The relative AMI risk in patients with and without cardiovascular risk factors was similarly elevated

Additional file 1: Table S1. of Evaluation of vaccination herd immunity effects for anogenital warts in a low coverage setting with human papillomavirus vaccine—an interrupted time series analysis from 2005 to 2010 using health insurance data

Person-Time, Cases and Incidence Estimates for 2005 to 2010 for Patients Aged 10 to 79 Years by Sex and Five Year Age Groups. (PDF 72 kb

Risk of Stroke after Herpes Zoster – Evidence from a German Self-Controlled Case-Series Study

BACKGROUND: Herpes zoster (HZ) is caused by reactivation of the latent varicella-zoster virus (VZV). A severe complication of HZ is VZV vasculopathy which can result in ischemic or hemorrhagic stroke. The aims of our study were to assess the risk of stroke after the onset of HZ and to investigate the roles of stroke subtype, HZ location and the time interval between HZ onset and stroke. METHODS: A self-controlled case-series study was performed on a cohort of patients with incident stroke recorded in the German Pharmacoepidemiological Research Database (GePaRD), which covers about 20 million persons throughout Germany. We estimated adjusted incidence rate ratios (IRR) by comparing the rate of stroke in risk periods (i.e., periods following HZ) with the rate of stroke in control periods (i.e., periods without HZ) in the same individuals, controlling for both time-invariant and major potentially time-variant confounders. RESULTS: The cohort included 124,462 stroke patients, of whom 6,035 (5%) had at least one HZ diagnosis identified in GePaRD either as main hospital discharge diagnosis or as HZ treated with antivirals. The risk of stroke was about 1.3 times higher in the risk periods 3 months after HZ onset, than in the control periods (IRR: 1.29; 95% confidence interval: 1.16–1.44). An elevated risk of similar magnitude was observed for ischemic and unspecified stroke, but a 1.5-fold higher risk was observed for hemorrhagic stroke. A slightly stronger effect on the risk of stroke was also observed during the 3 months after HZ ophthalmicus (HZO) onset (1.59; 1.10–2.32). The risk was highest 3 and 4 weeks after HZ onset and decreased thereafter. CONCLUSIONS: Our study corroborates an increased risk of stroke after HZ, which is highest 3 to 4 weeks after HZ onset. The results suggest that the risk is more pronounced after HZO and is numerically higher for hemorrhagic than for ischemic stroke