Biased Estimation of Adjusted Odds Ratios From Incomplete Covariate Data Due to Violation of the Missing at Random Assumption

We investigate the possible bias due to an erroneous missing at random assumption if adjusted odds ratios are estimated from incomplete covariate data using the maximum likelihood principle. A relation between complete case estimates and maximum likelihood estimates allows us to identify situations where the bias vanishes. Numerical computations demonstrate that the bias is most serious if the degree of the violation of the missing at random assumption depends on the value of the outcome variable or of the observed covariate. Implications for the analysis of prospective and retrospective studies are given

Age-at-death estimation in archaeological samples: Differences in population means resulting from different aging methods can be predicted from the mean ages of method-specific reference samples

Age mimicry is a well-known phenomenon in the application of osteological age-estimation methods. Age mimicry refers to the fact that predicting age-at-death from a specific trait (age indicator) based on the relation observed in a specific reference sample implies that age estimates to some degree reflect the age structure of the reference sample. In particular, the estimated population mean in a target population in which an age-estimation method is applied is shifted towards the mean in the method-specific reference sample. Consequently, differences in population means between different age-estimation methods in the same target population may be due to differences in mean age of the reference samples used to develop the age-estimation methods. We aim at quantifying the expected magnitude for such differences. Fifteen different traditional age-estimation methods were applied to a sample of 675 adult individuals from the early medieval cemetery of Mannheim-Seckenheim. The relation of the observed estimated population age means and the mean age in the reference samples was analyzed by linear regression. We find that up to 80% of the variation in the estimated population age means can be explained by the variation of the mean age in the reference samples. Furthermore, differences in the magnitude of 3 to 4 years in the mean age between two reference samples can imply a 1-year difference in estimated target population age means. Because large differences in mean age between reference samples used to develop different age-estimation methods are common, some care is needed in interpreting differences between individual age estimates or population mean age estimates in cases where different age-estimation techniques are used

Dose-response relationship between ambulatory load magnitude and load-induced changes in COMP in young healthy adults

To determine the dose-response relationship between ambulatory load magnitude during a walking stress test and load-induced changes in serum concentration of cartilage oligomeric matrix protein (sCOMP) in healthy subjects.; sCOMP was assessed before and after a 30-min walking stress test performed on three test days by 24 healthy volunteers. In each walking stress test, one of three ambulatory loads was applied in a block randomized crossover design: normal body weight (BW) (100%BW = normal load); reduced BW (80%BW = reduced load); increased BW (120%BW = increased load). Knee kinematics and ground reaction force (GRF) were measured using an inertial sensor gait analysis system and a pressure plate embedded in the treadmill.; Load-induced increases in sCOMP rose with increasing ambulatory load magnitude. Mean sCOMP levels increased immediately after the walking stress test by 26.8 ± 12.8%, 28.0 ± 13.3% and 37.3 ± 18.3% for the reduced, normal or increased load condition, respectively. Lower extremity kinematics did not differ between conditions.; The results of this study provide important evidence of a dose-response relationship between ambulatory load magnitude and load-induced changes in sCOMP. Our data suggests that in normal weight persons sCOMP levels are more sensitive to increased than to reduced load. The experimental framework presented here may form the basis for studying the relevance of the dose-response relationship between ambulatory load magnitude and load-induced changes in biomarkers involved in metabolism of healthy articular cartilage and after injury

Influence of magnetic fields on magneto-aerotaxis

The response of cells to changes in their physico-chemical micro-environment is essential to their survival. For example, bacterial magnetotaxis uses the Earth's magnetic field together with chemical sensing to help microorganisms move towards favoured habitats. The studies of such complex responses are lacking a method that permits the simultaneous mapping of the chemical environment and the response of the organisms, and the ability to generate a controlled physiological magnetic field. We have thus developed a multi-modal microscopy platform that fulfils these requirements. Using simultaneous fluorescence and high-speed imaging in conjunction with diffusion and aerotactic models, we characterized the magneto-aerotaxis of Magnetospirillum gryphiswaldense. We assessed the influence of the magnetic field (orientation; strength) on the formation and the dynamic of a micro-aerotactic band (size, dynamic, position). As previously described by models of magnetotaxis, the application of a magnetic field pointing towards the anoxic zone of an oxygen gradient results in an enhanced aerotaxis even down to Earth's magnetic field strength. We found that neither a ten-fold increase of the field strength nor a tilt of 45° resulted in a significant change of the aerotactic efficiency. However, when the field strength is zeroed or when the field angle is tilted to 90°, the magneto-aerotaxis efficiency is drastically reduced. The classical model of magneto-aerotaxis assumes a response proportional to the cosine of the angle difference between the directions of the oxygen gradient and that of the magnetic field. Our experimental evidence however shows that this behaviour is more complex than assumed in this model, thus opening up new avenues for research

The Basel-Gasfabrik research project: Addressing complex topics by an integrative approach

The late La Tène period site of Basel-Gasfabrik has been under investigation for more than a century. During that time, the unfortified settlement with its two cemeteries has yielded huge amounts of everyday and exceptional objects and features. Beginning in the mid-1970s, samples were systematically collected for scientific analyses during ongoing excavations, thus producing ideal preconditions for interdisciplinary research. In 2011-2014, the international research project “Approaching the living via the dead: human remains from the Late La Tène site Basel-Gasfabrik and their cultural-historical interpretations” addressed the multifarious ways in which the Iron Age community handled their deceased. The intense collaboration involved researchers from the Archäologische Bodenforschung Basel-Stadt and the universities of Basel (CH), Mainz and Freiburg i.Br. (D) and spanned eight disciplines: archaeology, archeoanthropology, archaeobotany, archaeozoology, geoarchaeology, biogeochemistry, molecular genetics and statistics. Research topics and theoretical frameworks were developed jointly as well as procedures to combine the disciplinary results in multistage processes in order to generate integrative syntheses of novel insights. The challenges and specific research potentials of the integrative approach may serve as a positive example for future interdisciplinary research project

Comparison of techniques for handling missing covariate data within prognostic modelling studies: a simulation study

Background: There is no consensus on the most appropriate approach to handle missing covariate data within prognostic modelling studies. Therefore a simulation study was performed to assess the effects of different missing data techniques on the performance of a prognostic model. Methods: Datasets were generated to resemble the skewed distributions seen in a motivating breast cancer example. Multivariate missing data were imposed on four covariates using four different mechanisms; missing completely at random (MCAR), missing at random (MAR), missing not at random (MNAR) and a combination of all three mechanisms. Five amounts of incomplete cases from 5% to 75% were considered. Complete case analysis (CC), single imputation (SI) and five multiple imputation (MI) techniques available within the R statistical software were investigated: a) data augmentation (DA) approach assuming a multivariate normal distribution, b) DA assuming a general location model, c) regression switching imputation, d) regression switching with predictive mean matching (MICE-PMM) and e) flexible additive imputation models. A Cox proportional hazards model was fitted and appropriate estimates for the regression coefficients and model performance measures were obtained. Results: Performing a CC analysis produced unbiased regression estimates, but inflated standard errors, which affected the significance of the covariates in the model with 25% or more missingness. Using SI, underestimated the variability; resulting in poor coverage even with 10% missingness. Of the MI approaches, applying MICE-PMM produced, in general, the least biased estimates and better coverage for the incomplete covariates and better model performance for all mechanisms. However, this MI approach still produced biased regression coefficient estimates for the incomplete skewed continuous covariates when 50% or more cases had missing data imposed with a MCAR, MAR or combined mechanism. When the missingness depended on the incomplete covariates, i.e. MNAR, estimates were biased with more than 10% incomplete cases for all MI approaches. Conclusion: The results from this simulation study suggest that performing MICE-PMM may be the preferred MI approach provided that less than 50% of the cases have missing data and the missing data are not MNAR

Vascular grading of angiogenesis: prognostic significance in breast cancer

The study aimed to evaluate the prognostic value of angiogenesis by vascular grading of primary breast tumours, and to evaluate the prognostic impact of adding the vascular grade to the Nottingham Prognostic Index (NPI). The investigation included 836 patients. The median follow-up time was 11 years and 4 months. The microvessels were immunohistochemically stained by antibodies against CD34. Angiogenesis was graded semiquantitatively by subjective scoring into three groups according to the expected number of microvessels in the most vascular tumour area. The vascular grading between observers was moderately reproduced (κ = 0.59). Vascular grade was significantly associated with axillary node involvement, tumour size, malignancy grade, oestrogen receptor status and histological type. In univariate analyses vascular grade significantly predicted recurrence free survival and overall survival for all patients (P< 0.0001), node-negative patients (P< 0.0001) and node-positive patients (P< 0.0001). Cox multivariate regression analysis showed that vascular grading contributed with independent prognostic value in all patients (P< 0.0001). A prognostic index including the vascular grade had clinical impact for 24% of the patients, who had a shift in prognostic group, as compared to NPI, and implied a better prognostic dissemination. We concluded that the angiogenesis determined by vascular grading has independent prognostic value of clinical relevance for patients with breast cancer. © 2000 Cancer Research Campaig

The impact of post-procedural complications on reimbursement, length of stay and mechanical ventilation among patients undergoing transcatheter aortic valve implantation in Germany

BACKGROUND: The impact of various post-procedural complications after transcatheter aortic valve implantation (TAVI) on resource use and their consequences in the German reimbursement system has still not been properly quantified. METHODS: In a retrospective observational study, we use data from the German DRG statistic on patient characteristics and in-hospital outcomes of all isolated TAVI procedures in 2013 (N = 9147). The impact of post-procedural complications on reimbursement, length of stay and mechanical ventilation was analyzed using both unadjusted and risk-adjusted linear and logistic regression analyses. RESULTS: A total of 235 (2.57%) strokes, 583 (6.37%) bleeding events, 474 (5.18%) cases of acute kidney injury and 1428 (15.61%) pacemaker implantations were documented. The predicted reimbursement of an uncomplicated TAVI procedure was €33,272, and bleeding events were associated with highest additional reimbursement (€12,839, p 48 h: OR 6.93, p 48 h: OR 5.73, p < 0.001). Pacemaker implantations, in contrast, were associated with comparably small increases in reimbursement (€662, p = 0.006) and length of stay (3.54 days, p = 0.006) and no impaired likelihood of mechanical ventilation more than 48 h (OR 1.22, p = 0.156). Interestingly, these complication-related consequences remain mostly unchanged after baseline risk-adjustment. CONCLUSIONS: Post procedural complications such as bleeding events, acute kidney injuries and strokes are associated with increased resource use and substantial amounts of additional reimbursement in Germany, which has important implications for decision making outside of the usual clinical sphere

Inter-rater agreement and reliability of the COSMIN (COnsensus-based Standards for the selection of health status Measurement Instruments) Checklist

<p>Abstract</p> <p>Background</p> <p>The COSMIN checklist is a tool for evaluating the methodological quality of studies on measurement properties of health-related patient-reported outcomes. The aim of this study is to determine the inter-rater agreement and reliability of each item score of the COSMIN checklist (n = 114).</p> <p>Methods</p> <p>75 articles evaluating measurement properties were randomly selected from the bibliographic database compiled by the Patient-Reported Outcome Measurement Group, Oxford, UK. Raters were asked to assess the methodological quality of three articles, using the COSMIN checklist. In a one-way design, percentage agreement and intraclass kappa coefficients or quadratic-weighted kappa coefficients were calculated for each item.</p> <p>Results</p> <p>88 raters participated. Of the 75 selected articles, 26 articles were rated by four to six participants, and 49 by two or three participants. Overall, percentage agreement was appropriate (68% was above 80% agreement), and the kappa coefficients for the COSMIN items were low (61% was below 0.40, 6% was above 0.75). Reasons for low inter-rater agreement were need for subjective judgement, and accustom to different standards, terminology and definitions.</p> <p>Conclusions</p> <p>Results indicated that raters often choose the same response option, but that it is difficult on item level to distinguish between articles. When using the COSMIN checklist in a systematic review, we recommend getting some training and experience, completing it by two independent raters, and reaching consensus on one final rating. Instructions for using the checklist are improved.</p