Biomedical subjects

M Hellmich

Publications and source records attributed to M Hellmich.

16 recordsLinked to original sources

PubMed2005

Closure procedures for monotone bi-factorial dose-response designs.

Two goals of multiple-dose factorial trials are (i) demonstrating improved effectiveness of a fixed combination over each of its components as well as (ii) identifying a safe and effective dose range. The authors address both goals though with focus on the second by closure procedures that guarantee strong control of the familywise error rate. Two different families of null hypotheses are investigated for bi-factorial dose-response designs that are monotone with respect to the matrix partial order. One is suitable to find the minimum effective dose(s) and the other one is large enough to identify the highest effective dose step(s). Likelihood ratio tests and appropriate multiple contrast tests are applied to an unbalanced clinical trial example taken from Hung (2000, Statistics in Medicine 19, 2079-2087). Full computer code written in the R language is available from the Internet.

Antihypertensive Agents↗

PubMed2005

Plasmacellular differentiation in extranodal marginal zone B cell lymphomas of the ocular adnexa: an analysis of the neoplastic plasma cell phenotype and its prognostic significance in 136 cases.

AIM: To determine (a) the expression of plasma cell related antigens in extranodal marginal zone B cell lymphomas (EMZL) of the ocular adnexa; and (b) the prognostic value of plasmacellular differentiation in these tumours. METHODS: A consecutive case series of 136 ocular adnexal EMZL obtained from three ocular pathology centres over 20 years was analysed retrospectively. An extensive immunohistochemical panel, including the plasma cell related antigens VS38c, CD38, CD138, multiple myeloma oncogene-1-protein (MUM1/IRF4), and CREB binding protein (CBP) was performed. EMZL were defined as "plasmacellular differentiated" on the basis of morphological features, evidence of cytoplasmic immunoglobulin, negativity for BSAP/PAX5, and expression of at least one of the investigated plasma cell related antigens. Controls included normal or hyperplastic lymphatic tissues. Detailed clinical data were collected for most patients, and compared with the results of immunohistochemistry. The end points considered for statistical analysis were development of local tumour recurrence, development of systemic disease, and lymphoma related death. RESULTS: 57 (42%) of the 136 ocular adnexal EMZL showed a plasmacellular differentiation; 45 of these plasmacytoid cases were primary tumours. In contrast with most admixed normal plasma cells, which displayed co-expression of MUM1/IRF4, Vs38c, CD38, CD138, and CBP, the plasmacellular differentiated EMZL tumour cells demonstrated co-expression of all five plasma cell related antigens in only six of 57 (11%) plasmacellular differentiated ocular adnexal EMZL. The most commonly expressed plasma cell related antigen was MUM1/IRF4, immunoreactivity being seen in 56/57 (98%) plasmacellular differentiated EMZL examined. Although the association of plasmacellular differentiation in primary ocular adnexal EMZL and disseminated disease was statistically significant on univariate analysis (p = 0.042), this was weaker on multivariate analysis. CONCLUSION: Plasmacellular differentiated tumour cells in EMZL demonstrate an aberrant immune profile for plasma cell related antigens when compared with normal plasma cells. On multivariate analysis, plasmacellular differentiation in ocular adnexal EMZL was not significantly associated with local recurrence, the development of systemic disease, or with lymphoma related death.

ADP-ribosyl Cyclase↗

PubMed2005

A ruler for interpreting diagnostic test results.

OBJECTIVES: Bayes' rule formalizes how the pre-test probability of having a condition of interest is changed by a diagnostic test result to yield the post-test probability of having the condition. To simplify this calculation a geometric solution in form of a ruler is presented. METHODS: Using odds and the likelihood ratio of a test result in favor of having the condition of interest, Bayes' rule can succinctly be expressed as "the posttest odds equals the pre-test odds times the likelihood ratio". Taking logarithms of both sides yields an additive equation. RESULTS: The additive log odds equation can easily be solved geometrically. We propose a ruler made of two scales to be adjusted laterally. A different, widely used solution in form of a nomogram was published by Fagan. CONCLUSIONS: Whilst use of the nomogram seems more obvious, the ruler may be easier to operate in clinical practice since no straight edge is needed for precise reading. Moreover, the ruler yields more intuitive results because it shows the change in probability due to a given test result on the same scale.

Bayes Theorem↗

PubMed2004

[Dry eye symptoms following retinal surgery and ocular tumour therapy].

BACKGROUND: Dry eye symptoms can often be observed following vitreo-retinal operations, however, little is known about the frequency and severity of these postoperative problems. METHODS: Examination of 140 patients following vitreo-retinal surgery ( n=31), brachytherapy ( n=76), proton beam radiation ( n=33) and controls ( n=54) using a questionnaire together with a clinical examination of the anterior segment, tear break-up time and a Schirmer test. RESULTS: Of the treated patients 63% complained of dry eye symptoms versus 40% of the controls ( p=0.004). The tear break-up time was decreased in treated patients ( p<0.001, medians: 15 vs. 20 s). No significant difference was seen on the Schirmer test ( p=0.825; medians: 12 vs. 12 mm). CONCLUSIONS: Dry eye symptoms are a common postoperative complication following vitreo-retinal surgery and ocular tumour therapy.

Adult↗

PubMed2004

Comparison of different isolation techniques prior gene expression profiling of blood derived cells: impact on physiological responses, on overall expression and the role of different cell types.

Owing to its clinical accessibility, peripheral blood is probably the best source for the assessment of differences or changes in gene expression associated with disease or drug response and therapy. Gene expression patterns in peripheral blood cells greatly depend on temporal and interindividual variations. However, technical aspects of blood sampling, isolation of cellular components, RNA isolation techniques and clinical aspects such as time to analysis and temperature during processing have been suggested to affect gene expression patterns. We therefore assessed gene expression patterns in peripheral blood from 29 healthy individuals by using Affymetrix microarrays. When RNA isolation was delayed for 20-24 h-a typical situation in clinical studies-gene signatures related to hypoxia were observed, and downregulation of genes associated with metabolism, cell cycle or apoptosis became dominant preventing the assessment of gene signatures of interindividual variation. Similarly, gene expression patterns were strongly dependent on choice of cell and RNA isolation and preparation techniques. We conclude that for large clinical studies, it is crucial to reduce maximally the time to RNA isolation. Furthermore, prior to study initiation, the cell type of interest should already be defined. Our data therefore will help to optimize clinical studies applying gene expression analysis of peripheral blood to exploit drug responses and to better understand changes associated with disease.

Adult↗

PubMed2003

Oncogenic human papillomavirus DNA loads in human immunodeficiency virus-positive women with high-grade cervical lesions are strongly elevated.

Human papillomavirus (HPV) DNA loads of six oncogenic HPV types were measured by real-time PCR in cervical scrapes of human immunodeficiency virus (HIV)-infected and uninfected women. In both groups, HPV loads increased with the grade of cervical disease. HIV infection did not affect HPV loads in low-grade lesions but was associated with significantly higher HPV loads in severe dysplasia; highest loads were found in advanced HIV disease. Our data reflect the aggressive course of HPV infection in HIV-positive women.

Adolescent↗

PubMed2003

Influence of displayed image size on radiographic detection of approximal caries.

OBJECTIVES: To evaluate the validity of approximal caries detection on digital bitewing radiographs displayed at different image sizes on either a cathode ray tube (CRT) monitor or a thin film transistor (TFT) monitor. METHODS: Five observers assessed digital radiographs of a charge-coupled device (CCD)-based sensor system (Sidexis) of 160 unrestored premolars and molars for approximal caries using a six category caries rating scale. Images were displayed at ratios of 1:1, 1:2 and 1:7 on a CRT monitor (Nokia 446 XS) and a TFT display (Panasonic LC 50S). Histological assessments of serial sections were used as the validation standard. Diagnostic accuracy was expressed as area under the receiver operating characteristic (ROC) curve (AUC) and was calculated at two levels of caries penetration: presence of caries (I) and presence of a lesion in the dentine (II). The influence of the factors "monitor type", "image size" and "validation threshold" were analysed with repeated measures analysis of variance. RESULTS: The ROC curve areas for approximal caries detection at both histological penetration levels were not influenced by the type of monitor display, whereas image size had a significant impact (P<0.01). AUCs for image size 1:7 (I, 0.62; II, 0.65) were smaller compared with ratios of 1:1 and 1:2 (P<0.01). No differences were observed between image size ratios 1:1 (I, 0.69; II, 0.74) and 1:2 (I, 0.68; II, 0.73). CONCLUSIONS: In this study, the type of monitor did not influence approximal caries detection on digital radiographs. Image sizes with a display ratio of 1:1 and 1:2 resulted in better diagnostic validity than those with a ratio of 1:7.

Analysis of Variance↗

PubMed2002

Influence of room lighting on grey-scale perception with a CRT-and a TFT monitor display.

OBJECTIVES: To determine the influence of ambient lighting on grey-scale perception using a cathode-ray tube (CRT) and a thin film transistor (TFT) computer display. METHODS: A cathode ray tube (Nokia XS 446) and a liquid crystal display (Panasonic LC 50S) were used at reduced room lighting (70 lux) and under conditions recommended for a dental operatory (1000 lux). Twenty-seven observers examined twice a modified SMPTE test pattern [0 to 255; 255 to 0] grey-scale values. The corresponding contrast differences were allocated to four ranges of grey levels (I: 0-63; II: 64-127; III: 128-191; IV: 192-255). The influences of monitor type, grey-scale range and illumination were evaluated by means of repeated measures analysis of variance. RESULTS: Detection of differences in monochromatic intensity was significantly earlier with reduced lighting (P<0.0001). When full ambient lighting was used, the TFT display was superior compared to the CRT monitor in ranges II and III (P<0.0001), whereas no differences could be detected for grey intensities between 0 and 63 (P=0.71) and between 192 and 255 (P=0.36). CONCLUSIONS: Background lighting hampers grey-scale perception on computer displays. In this study of one TFT and one CRT monitor, the TFT in full ambient lighting was associated with earlier detection of grey scale differences than CRT.

Adult↗

PubMed2001

Diagnosing schizophrenia in the initial prodromal phase.

BACKGROUND: In schizophrenia research, early detection in the initial prodrome before first psychotic episodes is a major topic. Therefore, the prognostic accuracy of initial prodromal symptoms was examined prospectively. METHODS: The study sample was composed of patients referred to outpatient departments of German psychiatric university departments, because of diagnostic problems, between 1987 and 1991. They were examined with the Bonn Scale for the Assessment of Basic Symptoms and the Ninth Version of the Present State Examination to detect an incipient schizophrenic disorder. Of 385 patients showing no schizophrenia-characteristic symptoms, between 1995 and 1998, 110 with and 50 without initial prodromal symptoms were followed up and reexamined with the same instruments for a transition to schizophrenia. RESULTS: During a mean follow-up period of 9.6 years, 79 (49.4%) of the 160 patients had transited to schizophrenia. The absence of prodromal symptoms excluded a subsequent schizophrenia with a probability of 96% (sensitivity: 0.98; false-negative predictions: 1.3%), whereas their presence predicted schizophrenia with a probability of 70% (specificity: 0.59; false-positive predictions: 20%). Certain disturbances, such as thought interference, disturbances of receptive language, or visual distortions, predicted schizophrenia, even with a probability up to 91% (specificity: 0.85-0.91; false-positive predictions: 1.9%-7.5%). CONCLUSIONS: The Bonn Scale for the Assessment of Basic Symptoms operationalization of prodromal symptoms performed well in the early detection of schizophrenia. It therefore might be useful for the prediction of the disorder, especially if it is further refined to select those items with particularly high prognostic accuracy.

Adult↗

PubMed2001

Alterations in expression of mucin, tenascin-c and syndecan-1 in the conjunctiva following retinal surgery and plaque radiotherapy.

PURPOSE: Disturbances of the ocular tear film layer and dry eye symptoms are common complications following retinal surgery and ocular tumour therapy. Examined were the histopathological changes of the conjunctiva following posterior segment surgery and plaque radiotherapy. METHODS: Biopsy specimens of the superior bulbar conjunctiva were obtained during cataract surgery between 2 weeks and 7 years following vitrectomy (n=92) or plaque radiotherapy for uveal melanoma (n=20) and from control subjects without previous ocular surgery (n=29). These were examined using conventional histology (HE, PAS, Van Gieson) and immunochemistry [APAAP, using antibodies directed against MUC1, MUC5AC, syndecan-1 and tenascin-C (TN-C)]. The histopathological changes were graded and statistical analysis was performed using Wilcoxon and Kruskal-Wallis rank sum tests. RESULTS: Conjunctival specimens of patients following vitrectomy or plaque radiotherapy for uveal melanoma demonstrated increased epithelial stratification, a significant decrease in the number of PAS- and MUC5AC-positive goblet cells, and distributional changes in expression of MUC1, syndecan- and TN-C within conjunctival epithelium or stroma. These alterations - in particular the goblet cell reduction and stromal fibrosis - were most prominent in those patients who had undergone radiotherapy. CONCLUSIONS: Posterior segment surgery can lead to morphological alterations of the conjunctiva and distributional changes in ocular mucins, which may cause dry eye symptoms.

Adult↗

PubMed2001

Scleral buckling versus primary vitrectomy in rhegmatogenous retinal detachment (SPR Study): design issues and implications. SPR Study report no. 1.

BACKGROUND: In patients with more complex rhegmatogenous retinal detachments (RRD) not complicated by proliferative vitreoretinopathy (PVR), the most appropriate operating method is controversial, and different surgeons use different techniques. The Scleral Buckling Versus Primary Vitrectomy in Rhegmatogenous Retinal Detachments Study (SPR Study) is designed to compare primary vitrectomy and scleral buckling techniques in these patients. METHODS: The SPR Study is a multicentre, randomised, controlled clinical trial stratified by lens status. Patients with RRD which is not complicated by PVR grade B or C and which cannot be treated with a single meridional sponge are randomised to either scleral buckling or pars plana vitrectomy as first surgical intervention. Four hundred consecutive patients are to be recruited per subtrial (phakic and aphakic/pseudophakic patients), and followed up for 1 year. The primary endpoint (functional outcome) is the change in visual acuity. Secondary endpoints (anatomical outcome) include postoperative PVR, retinal reattachment and the number of reoperations necessary to achieve retinal reattachment. Twenty-seven institutions (49 surgeons) in six European countries have been recruited for participation in the study. CONCLUSION: The SPR Study is the first randomised prospective clinical trial to compare scleral buckling and primary vitrectomy in patients with RRD. The results of this study should enable vitreoretinal surgeons to improve the surgical therapy of patients with the more complicated manifestations of RRD.

Humans↗

PubMed2001

Monitoring clinical trials with multiple arms.

In order to benefit from the substantial overhead expenses of a large group sequential clinical trial, the simultaneous investigation of several competing treatments becomes more popular. If at some interim analysis any treatment arm reveals itself to be inferior to any other treatment under investigation, this inferior arm may be or may even need to be dropped for ethical and/or economic reasons. Recently proposed methods for monitoring and analysis of group sequential clinical trials with multiple treatment arms are compared and discussed. The main focus of the article is on the application and extension of (adaptive) closed testing procedures in the group sequential setting that strongly control the familywise error rate. A numerical example is given for illustration.

Biometry↗

PubMed2001

Detection of porcine bone lesions and fissures: comparing digital selenium, digital luminescence, and analog film-screen radiography.

OBJECTIVE: The purpose of our study was to compare the diagnostic performance of a digital selenium detector (Thoravision) with that of analog film-screen systems and digital luminescence radiography in skeletal radiography for the detection of fissures and lesions in porcine bones. MATERIALS AND METHODS: One hundred bones taken from domestic pigs (50 ribs and 50 femurs) were divided into two equal groups. Fissures and bone lesions were created in 50 bones and 50 served as controls. The bones were examined using film-screen systems, digital luminescence radiography, and digital selenium radiography at various doses. Digital selenium radiography exposure values were adapted to the image geometry differing from the reference methods with a detector focus distance of 2.15 m. Four radiologists independently evaluated image quality and detectability of fissures and lesions on a five-point scale of confidence. Statistical evaluation was based on receiver operating characteristic curve analysis. RESULTS: Fissures and bone lesions were detected most reliably using the mammography film-screen system, but the difference in the results of the analog and digital reference images did not achieve statistical significance. CONCLUSION: Compared with analog film-screen systems, the lower spatial resolution of the digital selenium and digital luminescence radiography systems does not affect detectability of fissures and bone lesions in porcine bone. Selenium is effective in skeletal radiography for detecting fissures and bone lesions. With digital selenium and digital luminescence radiography, the surface dose can be cut to half that required for 200-speed film-screen systems without losing any diagnostically relevant information.

Animals↗

PubMed2000

[Is the diagnosis of schizophrenic illness possible in the initial prodromal phase to the first psychotic manifestation?].

In the international research on schizophrenia, the early detection and intervention already in the initial prodromal phase prior to the first psychotic manifestation has become one of the main aims in recent years. Therefore, in the present study, the diagnostic efficiency of initial prodromal symptoms was examined prospectively for the first time ever. At index-examination, patients were examined with the 'Bonn Scale for the Assessment of Basic Symptoms--BSABS' and the ninth version of the 'Present State Examination--PSE 9'. At that time, none of the 160 patients had shown psychotic symptoms, but in 110 of the cases prodromal symptoms were found. At the reexamination that took place in average 9.6 years later, patients were explored with regard to a meantime transition to a first psychotic episode applying the same instruments as at index-examination. 79 of the 160 patients (49.38%) had developed a schizophrenic disorder according to DSM-IV-criteria in the catamnestic interval. In general, the 66 assessed prodromal symptoms exhibited a high sensitivity (.98), a high negative predictive power (.96) and a low percentage of false-negative predictions (1.3%), but lower values of specificity (.59) and positive predictive power (.70) as well as a higher percentage of false-positive predictions (20.6%). However, for a subset of mainly cognitive prodromal symptoms with a sensitivity sufficient for diagnostic criteria, high specificities (.85-.91) and positive predictive powers (.71-.91) as well as satisfactory percentages of false-positive predictions (7.5%-1.9%), and good classification rates (81.25%) were found. The results show that the applied conceptualization of prodromal symptoms that originates in the German psychopathological tradition is indeed useful for an early detection of psychoses. By assessing those prodromal symptoms, which were proven to be highly predictive, a diagnosis of schizophrenic disorders already seems possible in the initial prodrome. Thus in future, an early intervention related to them might enable a prevention of first psychotic episodes.

Adolescent↗

PubMedDate not supplied

A Bayesian approach to a general regression model for ROC curves.

A fully Bayesian approach to a general nonlinear ordinal regression model for ROC-curve analysis is presented. Samples from the marginal posterior distributions of the model parameters are obtained by a Markov-chain Monte Carlo (MCMC) technique--Gibbs sampling. These samples facilitate the calculation of point estimates and credible regions as well as inferences for the associated areas under the ROC curves. The analysis of an example using freely available software shows that the use of noninformative vague prior distributions for all model parameters yields posterior summary statistics very similar to the conventional maximum-likelihood estimates. Clinically important advantages of this Bayesian approach are: the possible inclusion of prior knowledge and beliefs into the ROC analysis (via the prior distributions), the possible calculation of the posterior predictive distribution of a future patient outcome, and the potential to address questions such as: "What is the probability that a certain diagnostic test is better in one setting than in another?"

Bayes Theorem↗

PubMedDate not supplied

Bayesian approaches to meta-analysis of ROC curves.

A comparative review of important classic and Bayesian approaches to fixed-effects and random-effects meta-analysis of binormal ROC curves and areas underneath them is presented. The ROC analyses results of seven evaluation studies concerning the dexamethasone suppression test provide the basis for a worked example. Particular attention is given to fully Bayesian inference, a novelty in the ROC context, based on Gibbs samples from posterior distributions of hierarchical model parameters and related quantities. Fully Bayesian meta-analysis may properly account for the uncertainty associated with the model parameters, possibly incorporating prior knowledge and beliefs, and allows clinically intuitive predictions of unobserved study effects via calculation of posterior predictive densities. The effects of various different prior specifications (six noninformative as well as one informative) on the posterior estimates are investigated (sensitivity-analysis). Recommendations and suggestions for further research are made. Computer code for the more advanced methods may either be downloaded via the Internet or be found elsewhere.

Bayes Theorem↗