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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., (© 2022 The Authors. Pharmacoepidemiology and Drug Safety published by John Wiley & Sons Ltd.) more...

In late stage drug development, the experimental drug is tested in a diverse study population within the relevant indication. In order to receive marketing authorization, robust evidence for the therapeutic efficacy is crucial requiring investigation of treatment effects in well-defined subgroups. Conventionally, consistency analyses in subgroups have been performed by means of interaction tests. However, the interaction test can only reject the null hypothesis of equivalence and not confirm consistency. Simulation studies suggest that the interaction test has low power but can also be oversensitive depending on sample size-leading in combination with the actually ill-posed null hypothesis to findings regardless of clinical relevance. In order to overcome these disadvantages in the setup of binary endpoints, we propose to use a consistency test based on the interval inclusion principle, which is able to reject heterogeneity and confirm consistency of subgroup-specific treatment effects while controlling the type I error. This homogeneity test is based upon the deviation between overall treatment effect and subgroup-specific effects on the odds ratio scale and is compared with an equivalence test based on the ratio of both subgroup-specific effects. Performance of these consistency tests is assessed in a simulation study. In addition, the consistency tests are outlined for the relative risk regression. The proposed homogeneity test reaches sufficient power in realistic scenarios with small interactions. As expected, power decreases for unbalanced subgroups, lower sample sizes, and narrower margins. Severe interactions are covered by the null hypothesis and are more likely to be rejected the stronger they are., (© 2020 The Authors. Statistics in Medicine published by John Wiley & Sons Ltd.) more...

Background: Li-Fraumeni syndrome (LFS) is a high-risk cancer predisposition syndrome caused by pathogenic germline variants of TP53. Cancer surveillance has noted a significant survival advantage in individuals with LFS; however, little is known about the feasibility, acceptance, and psychosocial effects of such a program., Methods: Pathogenic TP53 germline variant carriers completed a 7-part questionnaire evaluating sociodemographics, cancer history, surveillance participation, reasons for nonadherence, worries, and distress adapted from the Cancer Worry Scale. Counselees' common concerns and suggestions were assessed in MAXQDA Analytics Pro 12., Results: Forty-nine participants (46 females and 3 males), aged 40.0 ± 12.6 years, formed the study population; 43 (88%) had a personal cancer history (including multiple cancers in 10 [20%]). Forty-three individuals participated (88%) in surveillance during the study or formerly. Willingness to undergo surveillance was influenced by satisfaction with genetic testing and counseling (P = .019 [Fisher-Yates test]) but not by sociodemographics, cancer history, or distress level. Almost one-third of the participants reported logistical difficulties in implementing surveillance because of the high frequency of medical visits, scheduling difficulties, and the travel distance to their surveillance providers. Self-reported distress and perceived emotional burden for family members and partners were moderate (median for self-reported distress, 3.3; median for perceived emotional burden, 3.0). For both, the interquartile range was moderate to very high (2.7-3.7 and 3.0-3.7, respectively)., Conclusions: Individuals with LFS require efficient counseling as well as an accessible, well-organized, interdisciplinary, standardized surveillance program to increase adherence and psychological coping., (© 2020 The Authors. Cancer published by Wiley Periodicals LLC on behalf of American Cancer Society.) more...

We compare the calibration and variability of risk prediction models that were estimated using various approaches for combining information on new predictors, termed 'markers', with parameter information available for other variables from an earlier model, which was estimated from a large data source. We assess the performance of risk prediction models updated based on likelihood ratio (LR) approaches that incorporate dependence between new and old risk factors as well as approaches that assume independence ('naive Bayes' methods). We study the impact of estimating the LR by (i) fitting a single model to cases and non-cases when the distribution of the new markers is in the exponential family or (ii) fitting separate models to cases and non-cases. We also evaluate a new constrained maximum likelihood method. We study updating the risk prediction model when the new data arise from a cohort and extend available methods to accommodate updating when the new data source is a case-control study. To create realistic correlations between predictors, we also based simulations on real data on response to antiviral therapy for hepatitis C. From these studies, we recommend the LR method fit using a single model or constrained maximum likelihood. Copyright © 2016 John Wiley & Sons, Ltd., (Copyright © 2016 John Wiley & Sons, Ltd.) more...

Recent reports have indicated that digital PCR may be useful for the noninvasive detection of fetal aneuploidies by the analysis of cell-free DNA and RNA in maternal plasma or serum. In this review we provide an insight into the underlying technology and its previous application in the determination of the allelic frequencies of oncogenic alterations in cancer specimens. We also provide an indication of how this new technology may prove useful for the detection of fetal aneuploidies and single gene Mendelian disorders., (Copyright (c) 2008 John Wiley & Sons, Ltd.) more...

Cell division during development in many cases generates daughter cells that differ not only in fate, but also in size. We investigate the mechanisms that ensure proper spindle positioning during such asymmetric divisions using the one-cell stage Caenorhabditis elegans embryo as a model system. We utilized a UV laser microbeam as an in vivo microtubule-severing device to probe the forces driving spindle positioning. Our results indicate that extra-spindle pulling forces acting on the spindle poles dictate spindle position along the anterior-posterior embryonic axis. Importantly, forces acting on the posterior spindle pole appear more extensive than those acting on the anterior one, thus explaining the overall posterior spindle displacement that leads to the asymmetric division of the wild-type one-cell stage embryo. In separate work, we analysed a locus called zyg-8, which plays a key role in ensuring proper spindle positioning. Our data show that zyg-8 is required to promote microtubule growth and/or stability during anaphase. We identified the molecular nature of the zyg-8 locus in the course of a large-scale RNAi-based functional genomics screen. ZYG-8 harbours two notable protein domains: a Ca2+/calmodulin-dependent kinase domain, and a domain related to doublecortin, a human microtubule-associated protein involved in neuronal migration. more...

An experimental subject sequentially receives different levels of a stimulus, and data are recorded on response or non-response to the stimulus. To ensure that the subject cannot predict the next stimulus level based on previous stimulus levels, a randomized design, based on a generalized Pólya urn model, is used to allocate the stimulus levels. The goal of the experiment is to elicit information efficiently about the relationship between stimulus level and response (either for an individual subject or a group of independent subjects), by estimating quantiles of the stimulus-response curve. Our design allocates stimulus levels unimodally and symmetrically around the unknown median of the stimulus-response curve. We discuss estimation under a broad family of distributions and also fully discuss design issues and options. This design was used for an experiment in neurophysiology in humans to estimate the timing of onset of kinesthetic stimuli. Such psychophysical studies can increase our understanding of normal and pathological function. We present data from that experiment. more...