Record linkage of claims and cancer registries data-Evaluation of a deterministic linkage approach based on indirect personal identifiers.

PURPOSE: In Germany, record linkage of claims and cancer registry data is cost- and time-consuming, since up until recently no unique personal identifier was available in both data sources. The aim of this study was to evaluate the feasibility and performance of a deterministic linkage procedure based on indirect personal identifiers included in the data sources. METHODS: We identified users of glucose-lowering drugs with residence in four federal states in Northern and Southern Germany (Bavaria, Bremen, Hamburg, Lower Saxony) in the German Pharmacoepidemiological Research Database (GePaRD) and assessed colorectal and thyroid cancer cases. Cancer registries of the federal states selected all colorectal and thyroid cancer cases between 2004 and 2015. A deterministic linkage approach was performed based on indirect personal identifiers such as year of birth, sex, area of residence, type of cancer and an absolute difference between the dates of cancer diagnosis in both data sources of at most 90 days. Results were compared to a probabilistic linkage using "direct" personal identifiers (gold standard). RESULTS: The deterministic linkage procedure yielded a sensitivity of 71.8% for colorectal cancer and 66.6% for thyroid cancer. For thyroid cancer, the sensitivity improved when using only inpatient diagnosis to define cancer in GePaRD (71.4%). Specificity was always above 99%. Using the probabilistic linkage to define cancer cases, the risk for colorectal cancer was estimated 10 percentage points lower than when using the deterministic approach. CONCLUSIONS: Sensitivity of the deterministic linkage approach appears to be too low to be considered as reasonable alternative to the probabilistic linkage procedure.

Second dose of measles-mumps-rubella-varicella vaccine (MMRV) and the risk of febrile convulsions.

INTRODUCTION: Studies have shown an increased risk of febrile convulsions (FC) after first immunization with the quadrivalent measles-mumps-rubella-varicella vaccine (MMRV) compared to a first dose of measles-mumps-rubella vaccine (MMR) only or in combination with separately administered varicella vaccine (MMR + V). Therefore, it is recommended to give MMR + V at first dose and MMRV or MMR + V at second dose. Little is known on the risk of FC after MMRV at second dose, especially whether the risk depends on age, sex, history of FC or type of first dose vaccine. METHODS: A retrospective cohort study using claims data from the German Pharmacoepidemiological Research database (GePaRD) was performed in children born between January 1st, 2004 and October 31st, 2015 who received two doses of MMRV, MMR + V or MMR. Cases were defined as hospitalization with a diagnosis of FC without neurological conditions coded as main discharge diagnosis. Unadjusted and adjusted odds ratios (OR) with 95% confidence intevals (CIs) were calculated to compare the risk of FC. Stratified analyses were performed to examine potential effect modification by age, sex, history of FC or type of first dose vaccine. RESULTS: In the first 30 days after second dose vaccination, 464 FCs were observed in a cohort of 528,639 children with a median age of 17 months. After adjustment for potential confounders, the adjusted OR for FC in the 30 days after vaccination was 1.25 (95% CI 0.67-2.30) for MMRV compared to MMR + V and 1.04 (0.82-1.32) for MMRV compared to MMR. History of FC was the most important risk factor with an OR of 36.26 (29.30-44.89). We found no effect modification by age, sex, history of FC, or type of first dose vaccine. CONCLUSION: Use of MMRV at second dose is not associated with an increased risk of FC compared to MMR + V or MMR, irrespective of age, sex, history of FC, or type of first dose vaccine.

[Linkage of claims data with data from epidemiological cancer registries: possibilities and limitations in the German federal states]. / Verknüpfung von Abrechnungsdaten gesetzlicher Krankenkassen mit Daten epidemiologischer Krebsregister: länderspezifische Möglichkeiten und Limitationen.

BACKGROUND: In recent years, there has been an increasing demand for the reuse of research data in accordance with the so-called FAIR principles. This would allow researchers to conduct projects on a broader data basis and to investigate new research questions by linking different data sources. OBJECTIVES: We explored if nationwide linking of claims data from statutory health insurances (SHI) with data from population-based cancer registries can be used to obtain additional information on cancer that is missing in claims data and to assess the validity of SHI tumour diagnoses. This paper focuses on describing the specific requirements of German federal states for such data linkage. MATERIALS AND METHODS: The Pharmacoepidemiological Research Database GePaRD at the Leibniz Institute for Prevention Research and Epidemiology - BIPS and six cancer registries were used as data sources. The logistically complex direct linkage was compared with a less complex indirect linkage. For this purpose, permission had to be obtained for GePaRD and for each cancer registry from the respective responsible authority. RESULTS: Regarding the linkage of cancer registry data with GePaRD, the cancer registries showed profound differences in the modalities for data provision, ranging from a complete rejection to an uncomplicated implementation of linkage procedures. DISCUSSION: In Germany, a consistent legal framework is needed to adequately enable the reuse and record linkage of personal health data for research purposes according to the FAIR principles. The new law on the consolidation of cancer registry data could provide a remedy regarding the linkage of cancer registry data with other data sources.

Avoiding Time-Related Biases: A Feasibility Study on Antidiabetic Drugs and Pancreatic Cancer Applying the Parametric g-Formula to a Large German Healthcare Database.

PURPOSE: Investigating intended or unintended effects of sustained drug use is of high clinical relevance but remains methodologically challenging. This feasibility study aims to evaluate the usefulness of the parametric g-formula within a target trial for application to an extensive healthcare database in order to address various sources of time-related biases and time-dependent confounding. PATIENTS AND METHODS: Based on the German Pharmacoepidemiological Research Database (GePaRD), we estimated the pancreatic cancer incidence comparing two hypothetical treatment strategies for type 2 diabetes mellitus (T2DM), i.e., (A) sustained metformin monotherapy vs (B) combination therapy with DPP-4 inhibitors after one year metformin monotherapy. We included 77,330 persons with T2DM who started metformin therapy at baseline between 2005 and 2011. Key aspects for avoiding time-related biases and time-dependent confounding were the emulation of a target trial over a 7-year follow-up period and application of the parametric g-formula. RESULTS: Over the 7-year follow-up period, 652 out of the 77,330 study subjects had a diagnosis of pancreatic cancer. Assuming no unobserved confounding, we found evidence that the metformin/DPP-4i combination therapy increased the risk of pancreatic cancer compared to a sustained metformin monotherapy (risk ratio: 1.47; 95% bootstrap CI: 1.07-1.94). The risk ratio decreased in sensitivity analyses addressing protopathic bias. CONCLUSION: While protopathic bias could not fully be ruled out, and computational challenges necessitated compromises in the analysis, the g-formula and target trial emulation proved useful: Self-inflicted biases were avoided, observed time-varying confounding was adjusted for, and the estimated risks have a clear causal interpretation.

How often are antidepressants prescribed off-label among older adults in Germany? A claims data analysis.

AIM: To estimate the extent of off-label prescribing of antidepressants in older adults and to characterize patients with off-label vs on-label prescriptions of antidepressants using a large German health claims database. METHODS: Using data from the German Pharmacoepidemiological Research Database (GePaRD), we conducted a cross-sectional study in adults aged 65 years or older with a dispensation of an antidepressant between 1 January 2009 and 31 December 2015 after a period of 365 days without such a dispensation. We assessed the overall and annual proportion of off-label prescriptions of antidepressants by class and individual substance. RESULTS: Among 263 276 incident users of antidepressants, the proportion of off-label prescribing was 43.6% (95% CI 43.4-43.8%) with little variation between 2009 and 2015 (42.2-44.4%). The proportion of off-label use was higher in men (49%) than women (41%). While the proportion of off-label prescriptions was highest for tri- and tetracyclic antidepressants with 56.2% (amitriptyline 54.6%, maximum 65.9% for trimipramine), it amounted to 41.8% for selective serotonin reuptake inhibitors (citalopram 41.6%, maximum 46.0% for escitalopram) and was 51.2% for mirtazapine. Indicators of overall morbidity were similar in both groups, eg, pain was coded in 72% of off-label users vs 77% of on-label users (insomnia 20% vs 24%). CONCLUSION: Our study suggests a high prevalence of off-label antidepressant use among older adults in Germany, which was not restricted to certain classes of antidepressants or individual antidepressants. Given the unclear risk-benefit ratio, studies investigating the safety of off-label use among older adults for individual antidepressants are urgently needed.

Risk of Acute Liver Injury in Agomelatine and Other Antidepressant Users in Four European Countries: A Cohort and Nested Case-Control Study Using Automated Health Data Sources.

BACKGROUND: Agomelatine is a melatonin receptor agonist and serotonin 5-HT2C receptor antagonist indicated for depression in adults. Hepatotoxic reactions like acute liver injury (ALI) are an identified risk in the European risk management plan for agomelatine. Hepatotoxic reactions have been reported for other antidepressants, but population studies quantifying these risks are scarce. Antidepressants are widely prescribed, and users often have risk factors for ALI (e.g. metabolic syndrome). OBJECTIVE: The goal was to estimate the risk of ALI associated with agomelatine and other antidepressants (fluoxetine, paroxetine, sertraline, escitalopram, mirtazapine, venlafaxine, duloxetine, and amitriptyline) when compared with citalopram in routine clinical practice. METHOD: A nested case-control study was conducted using data sources in Denmark, Germany, Spain, and Sweden (study period 2009-2014). Three ALI endpoints were defined using International Classification of Diseases (ICD) codes: primary (specific codes) and secondary (all codes) endpoints used only hospital discharge codes; the tertiary endpoint included both inpatient and outpatient settings (all codes). Validation of endpoints was implemented. Adjusted odds ratios (ORs) and 95% confidence intervals (CIs) for current use were estimated for each data source and combined. RESULTS: We evaluated 3,238,495 new antidepressant and 74,440 agomelatine users. For the primary endpoint, the OR for agomelatine versus citalopram was 0.48 (CI 0.13-1.71). Results were also < 1 when no exclusion criteria were applied (OR 0.37; CI 0.19-0.74), when all exclusion criteria except alcohol and drug abuse were applied (OR 0.47; CI 0.20-1.07), and for the secondary (OR 0.40; CI 0.05-3.11) and tertiary (OR 0.79; CI 0.50-1.25) endpoints. Regarding other antidepressants versus citalopram, most OR point estimates were also below one, although with varying widths of the 95% CIs. The result of the tertiary endpoint and the sensitivity analyses of the primary endpoint were the most precise. CONCLUSION: In this study, using citalopram as a comparator, agomelatine was not associated with an increased risk of ALI hospitalisation. The results for agomelatine should be interpreted in the context of the European risk minimisation measures in place. Those measures may have induced selective prescribing and could explain the lower risk of ALI for agomelatine when compared with citalopram. Most other antidepressants evaluated had ORs suggesting a lower risk than citalopram, but additional studies are required to confirm or refute these results.

Antidepressant use in Denmark, Germany, Spain, and Sweden between 2009 and 2014: Incidence and comorbidities of antidepressant initiators.

BACKGROUND: We aimed to describe patterns of use and characteristics of 10 commonly used antidepressants for the period 2009-2014 in Denmark, Germany, Spain, and Sweden. METHODS: Adult initiators from 2009 to 2014 of each study antidepressant were identified in four countries using five data sources: the Danish National registers, GePaRD (Germany), EpiChron (Aragon, Spain), SIDIAP (Catalonia, Spain), and the Swedish National Registers. The study included 10 study antidepressants: citalopram, escitalopram, fluoxetine, paroxetine, sertraline, duloxetine, venlafaxine, amitriptyline, mirtazapine, and agomelatine. RESULTS: Citalopram was the most prescribed study antidepressant, followed by mirtazapine. Paroxetine and agomelatine were the least prescribed antidepressants. Mirtazapine was widely used among older antidepressant initiators with higher percentages of comorbidities at baseline, and fluoxetine was used among young patients. Citalopram and amitriptyline had the lowest percentage of multiple antidepressant use in the 12 months prior to the current treatment episode, while agomelatine, duloxetine, and venlafaxine had the highest percentage of multiple antidepressant use in the year prior to the current treatment episode. LIMITATIONS: The most important limitations are exposure information based on filled prescriptions, focus on antidepressant initiators only, lack of information on the indication, and heterogeneity of the type of data across data sources. CONCLUSIONS: Results of this study including 4.8 million study antidepressant initiators of study antidepressants suggest that citalopram and mirtazapine are the most commonly prescribed antidepressants. Agomelatine and paroxetine were the least used antidepressants in the participating populations. Mirtazapine was the antidepressant most commonly prescribed among older antidepressant initiators with high percentage of comorbidities at baseline, whereas fluoxetine was commonly used among young patients.

Sequential tests for monitoring methods to detect elevated incidence - a simulation study.

BACKGROUND: Common cancer monitoring practice is seldom prospective and rather driven by public requests. This study aims to assess the performance of a recently developed prospective cancer monitoring method and the statistical tools used, in particular the sequential probability ratio test in regard to specificity, sensitivity, observation time and heterogeneity of size of the geographical unit. METHODS: A simulation study based on a predefined selection of cancer types, geographical unit and time period was set up. Based on the population structure of Lower Saxony the mean number of cases of three diagnoses were randomly assigned to the geographical units during 2008-2012. A two-stage monitoring procedure was then executed considering the standardized incidence ratio and sequential probability ratio test. Scenarios were constructed differing by the simulation of clusters, significance level and test parameter indicating a risk to be elevated. RESULTS: Performance strongly depended on the choice of the test parameter. If the expected numbers of cases were low, the significance level was not fully exhausted. Hence, the number of false positives was lower than the chosen significance level suggested, leading to a high specificity. Sensitivity increased with the expected number of cases and the amount of risk and decreased with the size of the geographical unit. CONCLUSIONS: The procedure showed some desirable properties and is ready to use for a few settings but demands adjustments for others. Future work might consider refinements of the geographical structure. Inhomogeneous unit size could be addressed by a flexible choice of the test parameter related to the observation time.