• Measuring inter-rater reliability for nominal data - which coefficients and confidence intervals are appropriate?

      Zapf, Antonia; Castell, Stefanie; Morawietz, Lars; Karch, André; Helmholtz Centre for infection research, Inhoffenstr. 7, 38124 Braunschweig, Germany. (2016)
      Reliability of measurements is a prerequisite of medical research. For nominal data, Fleiss' kappa (in the following labelled as Fleiss' K) and Krippendorff's alpha provide the highest flexibility of the available reliability measures with respect to number of raters and categories. Our aim was to investigate which measures and which confidence intervals provide the best statistical properties for the assessment of inter-rater reliability in different situations.
    • Mortality in the German Pharmacoepidemiological Research Database (GePaRD) compared to national data in Germany: results from a validation study.

      Ohlmeier, Christoph; Langner, Ingo; Hillebrand, Kathrin; Schmedt, Niklas; Riedel, Oliver; Garbe, Edeltraut (2015)
      Electronic healthcare databases are of increasing importance in health research and mortality is one of the most relevant outcomes. However, data in these databases need to be validated, since they are often generated for reimbursement purposes. The aims of this study were to compare mortality figures from the German Pharmacoepidemiological Research Database (GePaRD) on an aggregated level with external data from the Federal Statistical Office of Germany (FSOG) and to assess consistency of records of death from core data and hospital data within GePaRD.
    • Optimized Management of Endovascular Treatment for Acute Ischemic Stroke.

      Schregel, Katharina; Behme, Daniel; Tsogkas, Ioannis; Knauth, Michael; Maier, Ilko; Karch, André; Mikolajczyk, Rafael; Bähr, Mathias; Schäper, Jörn; Hinz, José; Liman, Jan; Psychogios, Marios-Nikos; HZI,Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7,38124 Braunschweig, Germany. (2018-01-18)
      This manuscript describes a streamlined protocol for the management of patients with acute ischemic stroke, which aims at the minimization of time from hospital admission to reperfusion. Rapid restoration of cerebral blood flow is essential for the outcomes of patients with acute ischemic stroke. Endovascular treatment (EVT) has become the standard of care to accomplish this in patients with acute stroke due to large vessel occlusion (LVO). To achieve reperfusion of ischemic brain regions as fast as possible, all in-hospital time delays have to be carefully avoided. Therefore, management of patients with acute ischemic stroke was optimized with an interdisciplinary standard operating procedure (SOP). Stroke neurologists, diagnostic as well as interventional neuroradiologists, and anesthesiologists streamlined all necessary processes from patient admission and diagnosis to EVT of eligible patients. Target times for every step were established. Actually achieved times were prospectively recorded along with clinical data and imaging scores for all endovascularly treated stroke patients. These data were regularly analyzed and discussed in interdisciplinary team meetings. Potential issues were evaluated and all staff involved was trained to adhere to the SOP. This streamlined patient management approach and enhanced interdisciplinary collaboration reduced time from patient admission to reperfusion significantly and was accompanied by a beneficial effect on clinical outcomes.
    • Partial verification bias and incorporation bias affected accuracy estimates of diagnostic studies for biomarkers that were part of an existing composite gold standard.

      Karch, Annika; Koch, Armin; Zapf, Antonia; Zerr, Inga; Karch, André; Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7, 38124 Braunschweig, Germany. (2016-10)
      To investigate how choice of gold standard biases estimates of sensitivity and specificity in studies reassessing the diagnostic accuracy of biomarkers that are already part of a lifetime composite gold standard (CGS).
    • Poor knowledge of vaccination recommendations and negative attitudes towards vaccinations are independently associated with poor vaccination uptake among adults - Findings of a population-based panel study in Lower Saxony, Germany.

      Akmatov, Manas K; Rübsamen, Nicole; Deyneko, Igor V; Karch, André; Mikolajczyk, Rafael T; Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7, 38124 Braunschweig, Germany. (2018)
      The aims of this study were to (a) assess knowledge of official vaccination recommendations and attitudes towards vaccinations among adults and (b) examine their association with vaccination uptake among adults.
    • Population-level impact, herd immunity, and elimination after human papillomavirus vaccination: a systematic review and meta-analysis of predictions from transmission-dynamic models.

      Brisson, Marc; Bénard, Élodie; Drolet, Mélanie; Bogaards, Johannes A; Baussano, Iacopo; Vänskä, Simopekka; Jit, Mark; Boily, Marie-Claude; Smith, Megan A; Berkhof, Johannes; Canfell, Karen; Chesson, Harrell W; Burger, Emily A; Choi, Yoon H; De Blasio, Birgitte Freiesleben; De Vlas, Sake J; Guzzetta, Giorgio; Hontelez, Jan A C; Horn, Johannes; Jepsen, Martin R; Kim, Jane J; Lazzarato, Fulvio; Matthijsse, Suzette M; Mikolajczyk, Rafael T; Pavelyev, Andrew; Pillsbury, Matthew; Shafer, Leigh Anne; Tully, Stephen P; Turner, Hugo C; Usher, Cara; Walsh, Cathal; Helmholtz Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7, 38124 Braunschweig, Germany. (2016-11)
      Modelling studies have been widely used to inform human papillomavirus (HPV) vaccination policy decisions; however, many models exist and it is not known whether they produce consistent predictions of population-level effectiveness and herd effects. We did a systematic review and meta-analysis of model predictions of the long-term population-level effectiveness of vaccination against HPV 16, 18, 6, and 11 infection in women and men, to examine the variability in predicted herd effects, incremental benefit of vaccinating boys, and potential for HPV-vaccine-type elimination.
    • Predictors of the patient-centered outcomes of surgical carpal tunnel release - a prospective cohort study.

      Conzen, Catharina; Conzen, Michael; Rübsamen, Nicole; Mikolajczyk, Rafael; Helmholtz Centre for infection research, Inhoffenstr. 7, 38124 Braunschweig, Germany. (2016)
      Carpal tunnel syndrome (CTS) causes a substantial burden of disease in society. While CTS can be resolved by surgical carpal tunnel release, it still remains unclear as to what degree outcomes depend on patients' characteristics. This study assesses patient-centered outcomes after surgical carpal tunnel release in a large outpatient clinic in Germany.
    • Proposing an empirically justified reference threshold for blood culture sampling rates in intensive care units.

      Karch, André; Castell, Stefanie; Schwab, Frank; Geffers, Christine; Bongartz, Hannah; Brunkhorst, Frank M; Gastmeier, Petra; Mikolajczyk, Rafael T; Helmholtz Centre for infection research, Inhoffenstr. 7, 38124 Braunschweig, Germany. (2015-02)
      Early and appropriate blood culture sampling is recommended as a standard of care for patients with suspected bloodstream infections (BSI) but is rarely taken into account when quality indicators for BSI are evaluated. To date, sampling of about 100 to 200 blood culture sets per 1,000 patient-days is recommended as the target range for blood culture rates. However, the empirical basis of this recommendation is not clear. The aim of the current study was to analyze the association between blood culture rates and observed BSI rates and to derive a reference threshold for blood culture rates in intensive care units (ICUs). This study is based on data from 223 ICUs taking part in the German hospital infection surveillance system. We applied locally weighted regression and segmented Poisson regression to assess the association between blood culture rates and BSI rates. Below 80 to 90 blood culture sets per 1,000 patient-days, observed BSI rates increased with increasing blood culture rates, while there was no further increase above this threshold. Segmented Poisson regression located the threshold at 87 (95% confidence interval, 54 to 120) blood culture sets per 1,000 patient-days. Only one-third of the investigated ICUs displayed blood culture rates above this threshold. We provided empirical justification for a blood culture target threshold in ICUs. In the majority of the studied ICUs, blood culture sampling rates were below this threshold. This suggests that a substantial fraction of BSI cases might remain undetected; reporting observed BSI rates as a quality indicator without sufficiently high blood culture rates might be misleading.
    • Regional variation in caesarean deliveries in Germany and its causes.

      Mikolajczyk, Rafael T; Schmedt, Niklas; Zhang, Jun; Lindemann, Christina; Langner, Ingo; Garbe, Edeltraut; Department of Clinical Epidemiology, Leibniz Institute for Prevention Research and Epidemiology-BIPS, Bremen, Germany. Rafael.mikolajczyk@helmholtz-hzi.de. (2013)
      Determinants of regional variation in caesarean sections can contribute explanations for the observed overall increasing trend of caesarean sections. We assessed which mechanism explains the higher rate of caesarean sections in the former West than East Germany: a more liberal use of caesarean sections in the case of relative indications or more common caesarean sections without indications.
    • The Risk of Hospitalizations with Injury Diagnoses in a Matched Cohort of Children and Adolescents with and without Attention Deficit/Hyperactivity Disorder in Germany: A Database Study.

      Lindemann, Christina; Langner, Ingo; Banaschewski, Tobias; Garbe, Edeltraut; Mikolajczyk, Rafael T; Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr.7, 38124 Braunschweig, Germany. (2017)
      Attention deficit/hyperactivity disorder (ADHD) is a common neuropsychiatric disorder in children and adolescents worldwide, and children with ADHD have elevated risk of injuries. Our aim was to assess the risk of hospitalizations with injury diagnoses and their various subtypes in children and adolescents with newly diagnosed ADHD compared to those without ADHD, as well as to study sex effects on this risk in the setting of the German health care system.
    • Sociodemographic determinants of spatial disparities in early childhood caries: An ecological analysis in Braunschweig, Germany.

      Meyer, Frederic; Karch, André; Schlinkmann, Kristin Maria; Dreesman, Johannes; Horn, Johannes; Rübsamen, Nicole; Sudradjat, Henny; Schubert, Rainer; Mikolajczyk, Rafael; Helmholtz Centre for infection research, Inhoffenstr.7, 38124 Braunschweig, Germany. (2017-05-26)
      To identify spatial disparities in dental caries experience (measured by dmft (decayed missing filled teeth) index) of children in the city of Braunschweig and to evaluate whether these disparities can be explained by sociodemographic characteristics.
    • Structure of the Escherichia coli ProQ RNA-binding protein.

      Gonzalez, Grecia M; Hardwick, Steven W; Maslen, Sarah L; Skehel, J Mark; Holmqvist, Erik; Vogel, Jörg; Bateman, Alex; Luisi, Ben F; Broadhurst, R William; Helmholtz Centre for infection research, Inhoffenstr. 7, 38124 Braunschweig, Germany. (2017-05)
      The protein ProQ has recently been identified as a global small noncoding RNA-binding protein in Salmonella, and a similar role is anticipated for its numerous homologs in divergent bacterial species. We report the solution structure of Escherichia coli ProQ, revealing an N-terminal FinO-like domain, a C-terminal domain that unexpectedly has a Tudor domain fold commonly found in eukaryotes, and an elongated bridging intradomain linker that is flexible but nonetheless incompressible. Structure-based sequence analysis suggests that the Tudor domain was acquired through horizontal gene transfer and gene fusion to the ancestral FinO-like domain. Through a combination of biochemical and biophysical approaches, we have mapped putative RNA-binding surfaces on all three domains of ProQ and modeled the protein's conformation in the apo and RNA-bound forms. Taken together, these data suggest how the FinO, Tudor, and linker domains of ProQ cooperate to recognize complex RNA structures and serve to promote RNA-mediated regulation.
    • Survival of children after liver transplantation for hepatocellular carcinoma.

      Baumann, Ulrich; Adam, René; Duvoux, Christophe; Mikolajczyk, Rafael; Karam, Vincent; D'Antiga, Lorenzo; Chardot, Christophe; Coker, Ahmet; Colledan, Michele; Ericzon, Bo-Goran; Line, Pål Dag; Hadzic, Nedim; Isoniemi, Helena; Klempnauer, Jürgen L; Reding, Raymond; McKiernan, Patrick J; McLin, Valérie; Paul, Andreas; Salizzoni, Mauro; Furtado, Emanuel San Bento; Schneeberger, Stefan; Karch, André; the European Liver and Intestine Transplant Association; Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7, 38124 Braunschweig, Germany. (2018-01-01)
      Hepatocellular carcinoma (HCC) in childhood differs from adult HCC because it is often associated with inherited liver disease. It is, however, unclear whether liver transplantation (LT) for HCC in childhood with or without associated inherited disease has a comparable outcome to adult HCC. On the basis of data from the European Liver Transplant Registry (ELTR), we aimed to investigate if there are differences in patient and graft survival after LT for HCC between children and adults and between patients with underlying inherited versus noninherited liver disease, respectively. We included all 175 children who underwent LT for HCC and were enrolled in ELTR between 1985 and 2012. Of these, 38 had an associated inherited liver disease. Adult HCC patients with (n = 79) and without (n = 316, matched by age, sex, and LT date) inherited liver disease served as an adult comparison population. We used multivariable piecewise Cox regression models with shared frailty terms (for LT center) to compare patient and graft survival between the different HCC groups. Survival analyses demonstrated a superior longterm survival of children with inherited liver disease when compared with children with HCC without inherited liver disease (hazard ratio [HR], 0.29; 95% CI, 0.10-0.90; P = 0.03) and adults with HCC with inherited liver disease (HR, 0.27; 95% CI, 0.06-1.25; P = 0.09). There was no survival difference between adults with and without inherited disease (HR, 1.05; 95% CI, 0.66-1.66; P = 0.84). In conclusion, the potential survival advantage of children with an HCC based on inherited disease should be acknowledged when considering transplantation and prioritization for these patients. Further prospective studies accounting for tumor size and extension at LT are necessary to fully interpret our findings. Liver Transplantation 24 246-255 2018 AASLD.
    • Systematic review of models assessing the economic value of routine varicella and herpes zoster vaccination in high-income countries.

      Damm, Oliver; Ultsch, Bernhard; Horn, Johannes; Mikolajczyk, Rafael T; Greiner, Wolfgang; Wichmann, Ole (2015)
      A systematic review was conducted to assess the cost-effectiveness of routine varicella and herpes zoster (HZ) vaccination in high-income countries estimated by modelling studies.
    • Top 25 Global Causes of Disability-Adjusted Life-Years (DALYs) in Children Younger Than 5 Years, Both Sexes, 1990 and 2013

      The Global Burden of Disease Pediatrics Collaboration; Karch, André; et al.; Institute for Health Metrics and Evaluation, University of Washington, 2301 Fifth Ave, Ste 600, Seattle, WA 98121 (JAMA Network, 2016-10-25)
      mportance The literature focuses on mortality among children younger than 5 years. Comparable information on nonfatal health outcomes among these children and the fatal and nonfatal burden of diseases and injuries among older children and adolescents is scarce. Objective To determine levels and trends in the fatal and nonfatal burden of diseases and injuries among younger children (aged <5 years), older children (aged 5-9 years), and adolescents (aged 10-19 years) between 1990 and 2013 in 188 countries from the Global Burden of Disease (GBD) 2013 study. Evidence Review Data from vital registration, verbal autopsy studies, maternal and child death surveillance, and other sources covering 14 244 site-years (ie, years of cause of death data by geography) from 1980 through 2013 were used to estimate cause-specific mortality. Data from 35 620 epidemiological sources were used to estimate the prevalence of the diseases and sequelae in the GBD 2013 study. Cause-specific mortality for most causes was estimated using the Cause of Death Ensemble Model strategy. For some infectious diseases (eg, HIV infection/AIDS, measles, hepatitis B) where the disease process is complex or the cause of death data were insufficient or unavailable, we used natural history models. For most nonfatal health outcomes, DisMod-MR 2.0, a Bayesian metaregression tool, was used to meta-analyze the epidemiological data to generate prevalence estimates. Findings Of the 7.7 (95% uncertainty interval [UI], 7.4-8.1) million deaths among children and adolescents globally in 2013, 6.28 million occurred among younger children, 0.48 million among older children, and 0.97 million among adolescents. In 2013, the leading causes of death were lower respiratory tract infections among younger children (905 059 deaths; 95% UI, 810 304-998 125), diarrheal diseases among older children (38 325 deaths; 95% UI, 30 365-47 678), and road injuries among adolescents (115 186 deaths; 95% UI, 105 185-124 870). Iron deficiency anemia was the leading cause of years lived with disability among children and adolescents, affecting 619 (95% UI, 618-621) million in 2013. Large between-country variations exist in mortality from leading causes among children and adolescents. Countries with rapid declines in all-cause mortality between 1990 and 2013 also experienced large declines in most leading causes of death, whereas countries with the slowest declines had stagnant or increasing trends in the leading causes of death. In 2013, Nigeria had a 12% global share of deaths from lower respiratory tract infections and a 38% global share of deaths from malaria. India had 33% of the world’s deaths from neonatal encephalopathy. Half of the world’s diarrheal deaths among children and adolescents occurred in just 5 countries: India, Democratic Republic of the Congo, Pakistan, Nigeria, and Ethiopia. Conclusions and Relevance Understanding the levels and trends of the leading causes of death and disability among children and adolescents is critical to guide investment and inform policies. Monitoring these trends over time is also key to understanding where interventions are having an impact. Proven interventions exist to prevent or treat the leading causes of unnecessary death and disability among children and adolescents. The findings presented here show that these are underused and give guidance to policy makers in countries where more attention is needed.
    • Trajectories of injecting behavior in the Amsterdam Cohort Study among drug users.

      Mikolajczyk, Rafael T; Horn, Johannes; Prins, Maria; Wiessing, Lucas; Kretzschmar, Mirjam; Helmholtz Centre for infection research, Inhoffenstr. 7, 38124 Braunschweig, Germany. (2014-11-01)
      Injecting frequency among people who inject drugs (IDU) can change along distinct trajectories, which can reflect on incidence of HIV and HCV infections. We aimed at assessing these patterns of longitudinal changes, their predictors and their association with the incidence of HIV and HCV.
    • Transcranial doppler sonography is not a valid diagnostic tool for detection of basilar artery stenosis or in-stent restenosis: a retrospective diagnostic study.

      Koh, Woori; Kallenberg, Kai; Karch, André; Frank, Tobias; Knauth, Michael; Bähr, Mathias; Liman, Jan; Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7, 38124 Braunschweig, Germany. (2017-05-11)
      There are contradictory reports concerning the validity of transcranial sonography (TCD and TCCS) for examinations of the basilar artery. Here we investigated sensitivity and specificity of transcranial sonography for the detection of basilar artery stenosis and in-stent-restenosis compared to cerebral angiography.
    • Twin and sibling studies using health insurance data: the example of attention deficit/hyperactivity disorder (ADHD).

      Langner, Ingo; Garbe, Edeltraut; Banaschewski, Tobias; Mikolajczyk, Rafael T; Department of Clinical Epidemiology, Leibniz-Institute for Prevention Research and Epidemiology, BIPS GmbH, Bremen, Germany. (2013)
      Twin studies are used to assess the contribution of genetic factors to the aetiology of diseases. To show the feasibility of such research on the basis of health insurance data, we analysed twin and sibling data on the attention deficit/hyperactivity disorder (ADHD) in the German Pharmacoepidemiological Research Database (GePaRD).
    • What is the optimal rate of caesarean section at population level? A systematic review of ecologic studies

      Betran, Ana P; Torloni, Maria R; Zhang, Jun; Ye, Jiangfeng; Mikolajczyk, Rafael; Deneux-Tharaux, Catherine; Oladapo, Olufemi T; Souza, João P; Tunçalp, Özge; Vogel, Joshua P; Gülmezoglu, Ahmet M (2015-06-21)
      Abstract In 1985, WHO stated that there was no justification for caesarean section (CS) rates higher than 10–15 % at population-level. While the CS rates worldwide have continued to increase in an unprecedented manner over the subsequent three decades, concern has been raised about the validity of the 1985 landmark statement. We conducted a systematic review to identify, critically appraise and synthesize the analyses of the ecologic association between CS rates and maternal, neonatal and infant outcomes. Four electronic databases were searched for ecologic studies published between 2000 and 2014 that analysed the possible association between CS rates and maternal, neonatal or infant mortality or morbidity. Two reviewers performed study selection, data extraction and quality assessment independently. We identified 11,832 unique citations and eight studies were included in the review. Seven studies correlated CS rates with maternal mortality, five with neonatal mortality, four with infant mortality, two with LBW and one with stillbirths. Except for one, all studies were cross-sectional in design and five were global analyses of national-level CS rates versus mortality outcomes. Although the overall quality of the studies was acceptable; only two studies controlled for socio-economic factors and none controlled for clinical or demographic characteristics of the population. In unadjusted analyses, authors found a strong inverse relationship between CS rates and the mortality outcomes so that maternal, neonatal and infant mortality decrease as CS rates increase up to a certain threshold. In the eight studies included in this review, this threshold was at CS rates between 9 and 16 %. However, in the two studies that adjusted for socio-economic factors, this relationship was either weakened or disappeared after controlling for these confounders. CS rates above the threshold of 9–16 % were not associated with decreases in mortality outcomes regardless of adjustments. Our findings could be interpreted to mean that at CS rates below this threshold, socio-economic development may be driving the ecologic association between CS rates and mortality. On the other hand, at rates higher than this threshold, there is no association between CS and mortality outcomes regardless of adjustment. The ecological association between CS rates and relevant morbidity outcomes needs to be evaluated before drawing more definite conclusions at population level.