Trends and current spectrum of contact allergy in Central Europe: results of the Information Network of Departments of Dermatology (IVDK) 2007-2018.

BACKGROUND: Changing patterns of exposure lead to changes in the spectrum of contact allergy in the general population and in patients patch tested for suspected contact allergy. The main contact allergens (haptens) are assembled in the so-called 'baseline series'. OBJECTIVES: To present the current spectrum of contact allergy to baseline series allergens, and its temporal development over the last 12 years, based on data collected by the 56 active departments of the trinational Information Network of Departments of Dermatology (IVDK). METHODS: Patch-test data, along with core demographic and clinical information, subdivided into 4-year periods for all patients patch tested with the baseline series in the IVDK, were analysed descriptively. Moreover, log-binomial regression analysis addressed temporal trends of specific contact allergies, adjusted for potentially confounding factors. RESULTS: Among the 125 436 patients tested with the German baseline series, the most common allergens were nickel (14·7%), fragrance mix I (8·1%), Myroxylon pereirae resin (7·5%) and cobalt (5·2%), with no conclusive trend. The rise and fall of contact allergy to methylchloroisothiazolinone/methylisothiazolinone (MI), following (self-) regulation in the European Union, reflected the MI contact allergy epidemic. Propolis showed a marked upward trend with a prevalence of 3·94% during the period 2015-2018. CONCLUSIONS: Decreases in sensitization prevalence likely reflect reduced exposure, with some lag, as seen with hydroxyisohexyl 3-cyclohexene carboxaldehyde. If no (sufficient) decrease can be observed despite interventions, such as for nickel and chromium, affected subgroups should be identified and their causative exposures explored. Finally, increases such as that observed with propolis, certainly warrant targeted investigation of the exposures driving sensitization, and possibly intervention. What is already known about this topic? Contact allergy is prevalent in the general population. Surveillance based on clinical data offers timely information on trends concerning certain allergens or subgroups at risk. What does this study add? This analysis provides an update of the current contact allergy prevalence in Central Europe, including time trends. This study describes the demographic and clinical profile of patients tested from 2007 to 2018. This research identifies contact allergens that require (further) preventive efforts. Linked Comment: Schuttelaar. Br J Dermatol 2020; 183:800-801.

Risk factors of polysensitization to contact allergens.

BACKGROUND: 'Polysensitization' (PS) is usually defined as contact sensitization to three or more unrelated haptens of the baseline patch test series. Despite PS being an important clinical phenotype indicating increased susceptibility to contact allergy, statistical approaches to analyse PS have hitherto been preliminary. OBJECTIVES: To apply an appropriate regression model for count data, namely, negative binomial hurdle regression, to a large set of clinical patch test data with the aim of estimating PS risk in more detail than previously achieved. METHODS: The detailed information provided by the hurdle model includes a separate estimation of an 'increment factor' quantifying the likelihood of further positive reactions, i.e. PS. Clinical data of 126 878 patients patch tested by departments comprising the IVDK (Information Network of Departments of Dermatology) network (www.ivdk.org) between 1995 and 2010 were included. RESULTS: Regarding anatomical sites as exposure (surrogate), the axillae and the feet were found to be strong PS risk factors. Moreover, age was a strong PS risk factor, and less so, female sex. In comparison, atopic eczema and occupational dermatitis were less important risk factors. Single allergens contributed to PS to a varying extent. CONCLUSIONS: The data presented point to some, very likely exposure-related, risk factors which need to be considered in future PS research, e.g. addressing the genetic basis for PS.

Assessing skin pigmentation in epidemiological studies: the reliability of measurements under different conditions.

BACKGROUND/PURPOSE: Different devices are used for the non-invasive measurement of (constitutive) skin pigmentation in (epidemiological) studies. Reproducibility of measurements with the Chromameter (CM, model CR 300, Minolta, Osaka) and the Reflectometer (RM, Courage & Khazaka, Cologne) has not yet been examined in detail and was addressed in a set of four experiments and studies respectively. METHODS: Regarding the CM, the Y value of the Yxy CIE 1931 colour system was utilized, representing lightness in this colour space, while the RM measured reflectance at 660 nm with a small bandwidth of 20 nm. Both devices measure reflectance on a scale from 0 to 100%, however, in different wavelength ranges. Between 3 and 20 repetitions were performed on standard grey scales and different sets of human volunteers, including RM measurements in a large epidemiological field study. RESULTS: While the coefficient of variation (V) increases and the intraclass correlation coefficient decreases from controlled laboratory to field conditions, reproducibility remained in a range considered acceptable, if adequate study conditions were maintained. In a direct comparison on human skin, V of the RM was significantly smaller than that of the CM. CONCLUSION: Both devices can be used confidently in field studies; however, based on considerations of skin optics and in view of slightly lesser variability, the RM may be preferable.

Recombinant human erythropoietin delays loss of gray matter in chronic schizophrenia.

Neurodevelopmental abnormalities together with neurodegenerative processes contribute to schizophrenia, an etiologically heterogeneous, complex disease phenotype that has been difficult to model in animals. The neurodegenerative component of schizophrenia is best documented by magnetic resonance imaging (MRI), demonstrating progressive cortical gray matter loss over time. No treatment exists to counteract this slowly proceeding atrophy. The hematopoietic growth factor erythropoietin (EPO) is neuroprotective in animals. Here, we show by voxel-based morphometry in 32 human subjects in a placebo-controlled study that weekly high-dose EPO for as little as 3 months halts the progressive atrophy in brain areas typically affected in schizophrenia, including hippocampus, amygdala, nucleus accumbens, and several neocortical areas. Specifically, gray matter protection is highly associated with improvement in attention and memory functions. These findings suggest that a neuroprotective strategy is effective against common pathophysiological features of schizophrenic patients, and strongly encourage follow-up studies to optimize EPO treatment dose and duration.

A comparison of patterns of sun protection during beach holidays and everyday outdoor activities in a population sample of young German children.

BACKGROUND: Reducing exposure to ultraviolet (UV) radiation is the main effective measure for preventing skin cancer. Educational campaigns targeting sun protection have been focused either on behaviour on the beach during the summer holiday alone, or during everyday outdoor activities of the children. Little is known about the comparison between these different settings. OBJECTIVES: To analyse whether parents apply similar protective measures to reduce UV exposure for their young children in different outdoor environments. METHODS: Families (n = 2619) with children aged 3-6 years (response: 64·7%) were enrolled in a population-based survey in the German city of Erlangen and its surrounding rural county. Using a self-administered standardized questionnaire parents gave information about demographic and photosensitivity data of their children, their knowledge about risk factors for skin cancer and their typical instructions given to their children when these played outside on a summer day in different outdoor environments. RESULTS: Significant discrepancies regarding the four UV protective measures (clothes, shade, sunhat, sunscreen) for children between an everyday outdoor setting and a holiday setting on the beach were observed. A high level of parental risk factor knowledge was significantly associated with a better protection for children in all four measures only on the beach. Photosensitivity and demographic characteristics had some impact on protective behaviour, too. Measures of sun protection were reduced with children's increasing age. CONCLUSIONS: Skin cancer prevention campaigns should target the encouragement of sun protection for children also in outdoor activities of daily living, not only during a summer holiday on the beach.

The importance of context information in the diagnostic rating of digital images of patch test reactions.

BACKGROUND: Patch test (PT) guidelines recommend classifying PT reactions based on morphological criteria only, i.e. irrespective of context information such as substance, concentration and vehicle. OBJECTIVES: To analyse reclassification of PT reactions after revelation of context information subsequent to an initial blinded reading. METHODS: One hundred and twenty-two participants (experienced dermatologists and researchers) rated 20 digital images of different PT reactions twice, first blinded, then unblinded regarding substance, concentration and vehicle. Agreement between both ratings was quantified with Cohen's kappa, and systematic differences statistically examined with tests for marginal homogeneity. RESULTS: Mostly, ratings remained stable, e.g. in > 90% of cases of images showing typical strong or extreme positive PT reactions. Reclassification was comparatively often observed in images depicting irritant reactions. Conversely, 16 of 122 participants re-rated doubtful reactions to thiuram mix and dichromate, respectively, as 'allergic' (weak or strong positive) after knowing the substance. CONCLUSIONS: The considerable proportion of participants who choose an 'allergic' rating, despite a morphological presentation definitely not justifying this, points to a conceptual problem of the PT reading scale: the mixing up of morphological classification and interpretation. We therefore suggest amending the scale. Moreover, standardization of PT reading can be improved by continual PT training sessions.

Outdoor work and skin cancer incidence: a registry-based study in Bavaria.

OBJECTIVE: To analyse the association between occupational ultraviolet (UV) light exposure and skin cancer (basal cell carcinoma, BCC; squamous cell carcinoma, SCC; cutaneous malignant melanoma, CMM) based on data from the Bavarian population-based cancer registry. METHODS: The population-based cancer registry of Bavaria (Germany) provided data on incident cases of BCC, SCC, and CMM, respectively, during the period 2001 until 2005. Eleven Bavarian districts with complete skin cancer registration were included in this analysis based on 2,156,336 person years. Cases were assigned to "indoor", "mixed indoor/outdoor", and "outdoor" exposure categories according to their job title. We computed age-specific and age-adjusted incidence rates of BCC (n = 1,641), SCC (n = 499), and CMM (n = 454) by work type, and the relative risk (RR) of skin cancer occurrence for "outdoor" and "mixed indoor/outdoor" workers, respectively, compared to "indoor" workers. RESULTS: The risk of BCC was substantially elevated in male (RR, 2.9; 95% CI, 2.2-3.9) and female (RR, 2.7; 95% CI, 1.8-4.1) outdoor workers compared to male and female indoor workers, respectively. We also found an elevated risk of similar magnitude for SCC in male (RR, 2.5; 95% CI, 1.4-4.7) and female (RR, 3.6; 95% CI, 1.6-8.1) outdoor workers compared to male and female indoor workers, respectively. CMM risk was not significantly associated with outdoor work. CONCLUSION: Our study confirms previous reports on the increased risk of BCC and SCC in outdoor workers compared to indoor workers.

Double-smoothing in kernel hazard rate estimation.

OBJECTIVES: In oncological studies, the hazard rate can be used to differentiate subgroups of the study population according to their patterns of survival risk over time. Nonparametric curve estimation has been suggested as an exploratory means of revealing such patterns. The decision about the type of smoothing parameter is critical for performance in practice. In this paper, we study data-adaptive smoothing. METHODS: A decade ago, the nearest-neighbor bandwidth was introduced for censored data in survival analysis. It is specified by one parameter, namely the number of nearest neighbors. Bandwidth selection in this setting has rarely been investigated, although the heuristical advantages over the frequently-studied fixed bandwidth are quite obvious. The asymptotical relationship between the fixed and the nearest-neighbor bandwidth can be used to generate novel approaches. RESULTS: We develop a new selection algorithm termed double-smoothing for the nearest-neighbor bandwidth in hazard rate estimation. Our approach uses a finite sample approximation of the asymptotical relationship between the fixed and nearest-neighbor bandwidth. By so doing, we identify the nearest-neighbor bandwidth as an additional smoothing step and achieve further data-adaption after fixed bandwidth smoothing. We illustrate the application of the new algorithm in a clinical study and compare the outcome to the traditional fixed bandwidth result, thus demonstrating the practical performance of the technique. CONCLUSION: The double-smoothing approach enlarges the methodological repertoire for selecting smoothing parameters in nonparametric hazard rate estimation. The slight increase in computational effort is rewarded with a substantial amount of estimation stability, thus demonstrating the benefit of the technique for biostatistical applications.

Flexible modeling of malignant melanoma survival.

OBJECTIVES: This paper compares the diagnostic capabilities of flexible ensemble methods modeling the survival time of melanoma patients in comparison to the well established proportional hazards model. Both a random forest type algorithm for censored data as well as a model combination of the proportional hazards model with recursive partitioning are investigated. METHODS: Benchmark experiments utilizing the integrated Brier score as a measure for goodness of prediction are the basis of the performance assessment for all competing algorithms. For the purpose of comparing regression relationships represented by the models under test, we describe fitted conditional survival functions by a univariate measure derived from the area under the curve. Based on this measure, we adapt a visualization technique useful for the inspection and comparison of model fits. RESULTS: For the data of malignant melanoma patients the predictive performance of the competing models is on par, allowing for a fair comparison of the fitted relationships. Newly introduced MODplots visualize differences in the fitting structure of the underlying models. CONCLUSION: The paper provides a framework for comparing the predictive and diagnostic performance of a parametric, a non-parametric and a combined approach.

The attributable risk in a multifactorial situation--evaluation of different methods of partitioning.

OBJECTIVES: Different approaches to partition the attributable risk into exposure-specific components are methodologically evaluated. METHODS: Two methods of partitioning the attributable risk in a multifactorial situation have been suggested. One is based on a solution adopted from game theory, the Shapley value, whereas the other recently suggested approach uses a heuristically motivated proportional weighting scheme. These two concepts are reviewed and compared in a situation with three exposure factors. A hypothetical numerical example is discussed illustrating differences in the case of complex interaction structures. RESULTS: The two methods are found to differ in two critical features that affect the outcome of partitioning: i) including or ignoring the full interaction structure between exposure factors involved in the partitioning, ii) using an equal or proportional weighting scheme for the marginal excess risks of the exposures. As a result, not only the individual partial attributable risks for the exposure factors may be quantitatively different between the methods, but also their ranking depends on the partitioning approach. CONCLUSIONS: The epidemiologic properties of the partitioning procedure based on the Shapley value are known and fit to the needs of epidemiologic applications. The alternative approach recently suggested can lead to considerably different results. As long as its epidemiologic properties are not fully understood, the traditional partitioning method should be given preference in practical applications.

Association between split selection instability and predictive error in survival trees.

OBJECTIVES: To evaluate split selection instability in six survival tree algorithms and its relationship with predictive error by means of a bootstrap study. METHODS: We study the following algorithms: logrank statistic with multivariate p-value adjustment without pruning (LR), Kaplan-Meier distance of survival curves (KM), martingale residuals (MR), Poisson regression for censored data (PR), within-node impurity (WI), and exponential log-likelihood loss (XL). With the exception of LR, initial trees are pruned by using split-complexity, and final trees are selected by means of cross-validation. We employ a real dataset from a clinical study of patients with gallbladder stones. The predictive error is evaluated using the integrated Brier score for censored data. The relationship between split selection instability and predictive error is evaluated by means of box-percentile plots, covariate and cutpoint selection entropy, and cutpoint selection coefficients of variation, respectively, in the root node. RESULTS: We found a positive association between covariate selection instability and predictive error in the root node. LR yields the lowest predictive error, while KM and MR yield the highest predictive error. CONCLUSIONS: The predictive error of survival trees is related to split selection instability. Based on the low predictive error of LR, we recommend the use of this algorithm for the construction of survival trees. Unpruned survival trees with multivariate p-value adjustment can perform equally well compared to pruned trees. The analysis of split selection instability can be used to communicate the results of tree-based analyses to clinicians and to support the application of survival trees.

Prior immunisation of patients with malignant melanoma with vaccinia or BCG is associated with better survival. An European Organization for Research and Treatment of Cancer cohort study on 542 patients.

There is increasing evidence that infections and vaccinations play an important role in the normal maturation of the immune system. It was therefore of interest to determine whether these immune events also affect the prognosis of melanoma patients. A cohort study of 542 melanoma patients in six European countries and Israel was conducted. Patients were followed up for a mean of 5 years and overall survival was recorded. Biometric evaluations included Kaplan-Meier estimates of survival over time and Hazard Ratios (HRs), taking into account all known prognostic factors. During the follow-up between 1993 and 2002, 182 of the 542 patients (34%) died. Survival curves, related to Breslow's thickness as the most important prognostic marker, were in accordance with those observed in previous studies where the cause of death was known to be due to disseminated melanoma. In a separate analysis of patients, vaccinated with vaccinia or Bacille Calmette-Guerin (BCG), HRs and the corresponding 95% Confidence Intervals (CIs) were 0.52 (0.34-0.79) and 0.69 (0.49-0.98), respectively. Joint analyses yielded HRs (and 95% CIs) of 0.55 (0.34-0.89) for patients vaccinated with vaccinia, 0.75 (0.30-1.86) with BCG, and 0.41 (0.25-0.69) with both vaccines. In contrast, infectious diseases occurring before the excision of the tumour had little, or, at the most, a minor influence on the outcome of the melanoma patients. These data reveal, for the first time, that vaccination with vaccinia in early life significantly prolongs the survival of patients with a malignant tumour after initial surgical management. BCG vaccination seems to have a similar, although weaker, effect. The underlying immune mechanisms involved remain to be determined.

A computer program to estimate power and relative efficiency of flexibly matched case-control studies.

OBJECTIVES: We recently introduced the concept of flexible matching strategies with varying proportions of a dichotomous matching factor among controls to increase power and efficiency of case-control studies. We now present a method and a computer program to calculate power and relative efficiency compared to an unmatched design varying the proportion of the matching factor in controls over all possible values from 0 to 100 percent. METHODS: For all these values, the program calculates the expected variance of the combined Mantel-Haenszel odds ratio and determines the power using the standard error of the expected combined Mantel-Haenszel odds ratio under the null hypothesis as derived from the Mantel-Haenszel test statistic without continuity correction. RESULTS: Thereby, the program allows estimating the optimal prevalence of the matching factor in selected controls for a given scenario which often differs from the prevalence in cases. It furthermore allows to estimate loss in power and efficiency compared to optimal matching by suboptimal matching. CONCLUSIONS: Estimations like these are helpful with respect to the decision when to stop efforts to optimize the degree of matching during the recruitment of controls. Our program will strongly facilitate assessing the benefits of flexible matching strategies.

Memorandum "Open Metadata". Open Access to Documentation Forms and Item Catalogs in Healthcare.

At present, most documentation forms and item catalogs in healthcare are not accessible to the public. This applies to assessment forms of routine patient care as well as case report forms (CRFs) of clinical and epidemiological studies. On behalf of the German chairs for Medical Informatics, Biometry and Epidemiology six recommendations to developers and users of documentation forms in healthcare were developed. Open access to medical documentation forms could substantially improve information systems in healthcare and medical research networks. Therefore these forms should be made available to the scientific community, their use should not be unduly restricted, they should be published in a sustainable way using international standards and sources of documentation forms should be referenced in scientific publications.

Epidemiology of ischemic stroke subtypes according to TOAST criteria: incidence, recurrence, and long-term survival in ischemic stroke subtypes: a population-based study.

BACKGROUND AND PURPOSE: The purpose of this study was to determine the incidence, recurrence, and long-term survival rates of ischemic stroke subtypes by a mechanism-based classification scheme (Trial of ORG 10172 in Acute Stroke Treatment, or TOAST). METHODS: We identified all 583 residents of the city of Erlangen, Bavaria, Germany, with a first ischemic stroke between 1994 and 1998. Multiple overlapping sources of information were used to ensure completeness of case ascertainment. The cause of ischemic stroke was classified according to the TOAST criteria. Patients were followed up at 3 months and 1 and 2 years after stroke onset. RESULTS: The age-standardized incidence rates for the European population (per 100 000) regarding ischemic stroke subtypes were as follows: cardioembolism, 30.2 (95% CI 25.6 to 35.7); small-artery occlusion, 25.8 (95% CI 21.5 to 30.9); and large-artery atherosclerosis, 15.3 (95% CI 12 to 19.3). When age-adjusted to the European population, the incidence rate for large-artery atherosclerosis was more than twice as high for men than for women (23.6/100 000 versus 9.2/100 000). Two years after onset, patients in the small-artery occlusion subgroup were 3 times more likely to be alive than those with cardioembolism. Ischemic stroke subtype according to the TOAST criteria was a significant predictor for long-term survival, whereas subtype was not a significant predictor of long-term recurrence up to 2 years, both before and after adjustment for age and sex. CONCLUSIONS: Epidemiological observational studies that possess wide access to appropriate diagnostic technologies and apply standardized etiologic classifications provide a much better understanding of underlying risk factors for initial stroke, recurrence, and mortality.

Period analysis for 'up-to-date' cancer survival data: theory, empirical evaluation, computational realisation and applications.

Long-term survival rates are the most commonly used outcome measures for patients with cancer. However, traditional long-term survival statistics, which are derived by cohort-based types of analysis, essentially reflect the survival expectations of patients diagnosed many years ago. They are therefore often severely outdated at the time they become available. A couple of years ago, a new method of survival analysis, denoted period analysis, has been introduced to derive more 'up-to-date' estimates of long-term survival rates. We give a comprehensive review of the new methodology, its statistical background, empirical evaluation, computational realisation and applications. We conclude that period analysis is a powerful tool to provide more 'up-to-date' cancer survival rates. More widespread use by cancer registries should help to increase the use of cancer survival statistics for patients, clinicians, and public health authorities.

A computer program for period analysis of cancer patient survival.

Monitoring of long-term survival rates, which is now routinely performed by many cancer registries throughout the world, should be as up-to-date as possible. A few years ago, a new method of survival analysis, denoted period analysis, has been proposed which provides more up-to-date estimates of long-term survival rates than traditional survival analysis by exclusively reflecting the survival experience of patients within a recent calendar period. However, application of this method has so far been hindered by the lack of pertinent computer programs. In this paper, we present a simple and easy-to-use computer program (SAS macro) that enables one to carry out period analysis (as well as conventional analysis) of both absolute and relative survival rates with the type of data commonly available in population-based cancer registries. We illustrate application of the program with examples from the nationwide Finnish Cancer Registry.

Impact of vaccinations and infectious diseases on the risk of melanoma--evaluation of an EORTC case-control study.

A significant correlation between a reduced risk of melanoma and BCG and vaccinia vaccination in early childhood or infectious diseases later in life has already been reported from the FEBrile Infections and Melanoma (FEBIM) multicentre case-control study. This correlation is further evaluated in this study based on 603 incident cases of malignant melanoma and 627 population controls in six European countries and Israel by means of a joint analysis of the influence of vaccinations and infectious diseases. In addition, the previously unconsidered impact of influenza vaccinations is evaluated for the whole study population. The strong effects of the frequently given BCG and vaccinia vaccinations in early childhood, as well as of uncommon previous severe infectious diseases, were apparently not cumulative. With the Odds Ratio (OR) being set at 1 in the absence of vaccinations and infectious diseases, the OR dropped to 0.37 (95% Confidence Interval (CI): 0.10-1.42) when subjects had experienced one or more severe infectious diseases, associated with a fever of > 38.5 degrees C, and had not been vaccinated with BCG or vaccinia. The OR was 0.29 (CI: 0.15-0.57) in those who had had a severe infectious disease and were vaccinated with either BCG or vaccinia and 0.33 (CI: 0.17-0.65) for those with 1 or more severe infectious diseases and who had received both vaccinations. We conclude that both vaccinations as well as previous episodes of having a severe infectious disease induced the same protective mechanism with regards to the risk of melanoma. Because of a 'masking effect' by the vaccinia vaccination, the protective effect of the BCG vaccination and of certain infectious diseases against cancer has remained undetected. The vaccinations contributed more to the protection of the population than a previous episode of having an infectious disease. In view of the termination of vaccinations with vaccinia in all countries and of BCG in many of them, these findings call for a re-evaluation of vaccination strategies.

Diagnosis and management of hypertension by physicians in the Federal Republic of Germany.

Diagnosis and management of hypertension by physicians in two large cities in the northwest of Germany were studied in 1988. Three hundred and fifteen out-of-hospital physicians (71%) responded to a mailed questionnaire. Sixty-eight per cent reported measuring blood pressure at almost each patient visit and 36% involved allied health professionals in the measurement process. Only 63% used disappearance of sound for the diastolic reading (phase V). A comparison with US data from 1987 showed that German physicians started drug therapy at higher levels of diastolic blood pressure than their American colleagues. Only 43% of the German physicians initiated antihypertensive medication at diastolic blood pressure values below 100 mmHg; this compares with 92% for US physicians. In Germany, beta-blockers were clearly preferred as step-one therapy for young patients, while diuretics were prescribed for the majority of the older patients. Forty per cent reported reducing or stopping antihypertensive medication when the blood pressure was controlled.