Biomedical subjects

Werner Brannath

Publications and source records attributed to Werner Brannath.

18 recordsLinked to original sources

PubMed2026

Family-Wise Error Rate Control in Clinical Trials With Overlapping Populations.

We consider clinical trials with multiple, overlapping patient populations that test multiple treatment policies specifically tailored to these populations. Such designs may lead to multiplicity issues, as false statements will affect several populations. For type I error control, often the family-wise error rate (FWER) is controlled, which is the probability to reject at least one true null hypothesis. If the joint distribution of the test statistics is known, the FWER level can be exhausted by determining critical values or adjusted-levels. The adjustment is typically done under the common ANOVA assumptions. However, the performed tests are then only valid under the rather strong assumption of homogeneous null effects, that is, when the null hypothesis applies to all subpopulations and their intersections. We show that under cancelling null effects, when heterogeneous effects cancel out in some or all subpopulations, this procedure does not provide FWER control. We also suggest different alternatives and compare them in terms of FWER control and their power.

Humans↗

PubMed2007

25-gauge vs 20-gauge system for pars plana vitrectomy: a prospective randomised clinical trial.

AIM: To compare 25-gauge vs 20-gauge system for pars plana vitrectomy in a prospective, randomised, controlled clinical trial. METHODS: Three-port pars plana vitrectomy was performed in 60 patients belonging to 2 groups. Evaluations were performed preoperatively, intraoperatively, during the first three postoperative days, at 1 week, and at 1 and 3 months. The main outcome measure was time for surgery, divided into duration of wound opening, vitrectomy, retinal manipulation and wound closure. RESULTS: The total duration of surgery showed no significant difference between the groups (p = 0.67). The 25-gauge group showed significantly shorter duration of wound opening (p<0.001) and wound closure (p<0.001). In contrast, the vitrectomy duration was significantly longer in the 25-gauge group (p<0.001). Conjunctival injection and subjective postoperative pain showed significantly lower irritation in the 25-gauge group (p<0.001 for both). CONCLUSION: The 25-gauge vitrectomy system offered significantly improved patient comfort during the first postoperative week. The smaller surgical openings facilitated wound healing and minimised pain. Duration of surgery was comparable between the two systems-the shorter time needed for wound opening and closure in the 25-gauge group being equalised by the longer vitrectomy duration. Intraoperative as well as retinal manipulation and illumination caused more surgical difficulties using the 25-gauge system.

Epiretinal Membrane↗

PubMed2006

Estimation in flexible two stage designs.

Adaptive test designs for clinical trials allow for a wide range of data driven design adaptations using all information gathered until an interim analysis. The basic principle is to use a test statistics which is invariant with respect to the design adaptations under the null hypothesis. This allows for a control of the type I error rate for the primary hypothesis even for adaptations not specified a priori in the study protocol. Estimation is usually another important part of a clinical trial, however, is more difficult in adaptive designs. In this research paper we give an overview of point and interval estimates for flexible designs and compare methods for typical sample size rules. We also make some proposals for confidence intervals which have nominal coverage probability also after an unforeseen design adaptation and which contain the maximum likelihood estimate and the usual unadjusted confidence interval.

Clinical Trials as Topic↗

PubMed2006

An adaptive hierarchical test procedure for selecting safe and efficient treatments.

We consider the situation where during a multiple treatment (dose) control comparison high doses are truncated because of lack of safety and low doses are truncated because of lack of efficacy, e.g., by decisions of a data safety monitoring committee in multiple interim looks. We investigate the properties of a hierarchical test procedure for the efficacy outcome in the set of doses carried on until the end of the trial, starting with the highest selected dose group to be compared with the placebo at the full level alpha. Left truncation, i.e., dropping doses in a sequence starting with the lowest dose, does not inflate the type I error rate. It is shown that right truncation does not inflate the type I error if efficacy and toxicity are positively related and dose selection is based on monotone functions of the safety data. A positive relation is given e.g. in the case where the efficacy and toxicity data are normally distributed with a positive pairwise correlation. A positive relation also applies if the probability for an adverse event is increasing with a normally distributed efficacy outcome. The properties of such truncation procedures are investigated by simulations. There is a conflict between achieving a small number of unsafely treated patients and a high power to detect safe and efficient doses. We also investigated a procedure to increase power where a reallocation of the sample size to the truncated treatments and the control remaining at the following stages is performed.

Biometry↗

PubMed2006

What affects the recurrence and clinical outcome of pigmented villonodular synovitis?

UNLABELLED: Studies investigating the outcome of pigmented villonodular synovitis have been restricted to certain locations or types of the disease and have not provided adequate documentation of followup. We asked the following questions: What were the recurrence rates especially when considering location and type of pigmented villonodular synovitis?; What was the long-term clinical outcome?; and Was MR imaging essential for the correct diagnosis? We retrospectively reviewed 42 of 53 consecutive patients primarily treated at our institution (19 diffuse lesions and 23 nodular lesions in 19 large joints and 23 digits of the hands or feet). Ten patients had recurrences after an average followup of 80 months (range, 26-293.8 months). Recurrences were more frequent for the diffuse type than the nodular type and in large joints rather than in digits. The average Enneking score was 92% of normal limb function indicating that surgical treatment led to good functional results. Preoperative magnetic resonance imaging results corresponded well with histologic diagnoses and intraoperative findings. LEVEL OF EVIDENCE: Therapeutic Level IV.

Adolescent↗

PubMed2005

Testing and estimation in flexible group sequential designs with adaptive treatment selection.

Integrating selection and confirmation phases into a single trial can expedite the development of new treatments and allows to use all accumulated data in the decision process. In this paper we review adaptive treatment selection based on combination tests and propose overall adjusted p-values and simultaneous confidence intervals. Also point estimation in adaptive trials is considered. The methodology is illustrated in a detailed example based on an actual planned study.

Austria↗

PubMed2005

Mcl-1, vascular endothelial growth factor-R2, and 14-3-3sigma expression might predict primary response against radiotherapy and chemotherapy in patients with locally advanced squamous cell carcinomas of the head and neck.

PURPOSE: This study was done to explore whether the expression of a selected set of proteins could predict primary response to radiotherapy or concomitant radiotherapy and chemotherapy in patients with advanced head and neck cancer. EXPERIMENTAL DESIGN: Forty-three pretreatment tumor biopsies were taken during diagnostic panendoscopy and examined for Mcl-1, vascular endothelial growth factor (VEGF)-R2, CD9, and 14-3-3sigma expression by immunohistochemistry. Forty-three patients underwent primary radiotherapy, of which, 29 patients received concomitant chemotherapy (low dose daily cisplatin, mitomycin C bolus). The primary end-point was locoregional tumor control 6 months after completion of radiotherapy. Mcl-1, VEGF-R2, CD9, and 14-3-3sigma expression were correlated with patients' primary response to radiotherapy and chemotherapy and with established clinicopathologic variables. RESULTS: Thirty complete and 13 partial responses were observed in our patient group. High expression levels of Mcl-1 (P=0.021), VEGF-R2 (P=0.032), and 14-3-3sigma (P=0.013), but not of CD9, in tumor biopsies was correlated with complete response. Overexpression of at least two of the three aforementioned proteins in pretreatment biopsies predicted-with a likelihood of 80%-whether a patient would achieve complete response to radiotherapy and chemotherapy. However, if only one of these proteins is overexpressed, there is a likelihood of 84.6% that this patient would not completely respond to therapy. CONCLUSION: Determining the expression levels of Mcl-1, VEGF-R2, and 14-3-3sigma may be helpful in predicting the early clinical response in head and neck tumor patients receiving primary radiotherapy and chemotherapy and may further allow a pretherapeutic selection of patients.

14-3-3 Proteins↗

PubMed2005

Modification of the Constant-Murley shoulder score-introduction of the individual relative Constant score Individual shoulder assessment.

The Constant-Murley shoulder assessment score has proven to be a valuable diagnostic instrument. Thus, in the literature it has been mentioned that the clinical accuracy of this score varies especially when comparing patients in larger, inhomogeneous patient groups. The "relative Constant score" (CS(rel)) tries to minimize these problems by using reference parameters out of healthy age and gender related control groups. The authors of this study tried to show that it is even more accurate to use the functional performance of the uninjured collateral shoulder of the same individual as reference, introducing the "individual relative Constant score" (CS(indiv)). The CS(indiv) and the CS(rel) were compared for 125 consecutive patients with shoulder disorders, and a group of 125 healthy volunteers as a control group. In a non-parametric comparison of the reciever operating characteristics the CS(indiv) shows the higher ability to discriminate between patients and healthy volunteers (p=0.004). This indicates that the individual relative Constant score gives a more accurate view about the functional result for shoulder disorders. It is expected to be more reliable for larger and incoherent patient populations, because specific interindividual differences, regarding the patient's age, gender and constitution are eliminated as well as other individual physiological parameters.

Adult↗

PubMed2005

Components of behavioral pathology in dementia.

OBJECTIVE: The purpose of this study was to examine the occurence of the noncognitive behavioral and psychological symptoms and signs of dementia in a geriatric chronic-care hospital and to separate agitated and affective components of behavioral pathology using factor analysis. METHODS: The frequency and severity of Alzheimer's disease, vascular dementia, mixed dementia and Lewy Body dementia was assessed in 145 consecutive residents of a chronic-care hospital. The presence of noncognitive behavioral symptoms was evaluated with the Behavioral Pathology in Alzheimer's Disease Rating Scale (BEHAVE-AD) and the Cohen-Mansfield Agitation Inventory (CMAI). A Factor analysis on the BEHAVE-AD subscores was performed to create symptom clusters. Analysis of covariance and post hoc tests were used to compare means of factor variables between different types of dementia. RESULTS: Statistical analysis showed a significant correlation between severity of dementia and BEHAVE-AD total score and between severity of dementia and CMAI total score. Factor analysis with Varimax rotation revealed the presence of three behavioral subsyndromes: agitation, affectivity and day/night disturbances. CONCLUSIONS: The finding of three factors of behavioral pathology in demented patients reflects the possibility that different etiological mechanisms could explain the expression of the symptoms and signs of psychosis in demented patients.

Affective Symptoms↗

PubMed2005

Plasma levels of polyunsaturated fatty acids in children with atopic dermatitis and in atopic and nonatopic controls.

BACKGROUND: Atopic dermatitis has been thought to be associated with a disturbance in n-6 polyunsaturated fatty acid (PUFA) metabolism, but randomized trials investigating the clinical efficacy of oral supplementation with gammalinolenic acid have revealed conflicting results. AIM OF THE STUDY: To re-investigate the proposed linkage between PUFA dysregulation and atopic dermatitis. MATERIALS AND METHODS: Plasma levels of linoleic acid (LA), gammalinolenic acid (GLA), dihomogammalinolenic acid (DGLA) and arachidonic acid (AA) were measured using HPLC in 22 children with atopic dermatitis. Patients were subdivided into those with elevated total serum IgE (group A, n = 15, IgE > +1 SD of age-specific normal values) and those with normal IgE (group B, n = 7) and compared with children suffering from allergic rhinitis/asthma (group C, n = 8) and with non-atopic controls (group D, n = 6). RESULTS: GLA levels were significantly lower (p < 0.05) in eczema patients with elevated IgE (A, 0.19 +/- 0.06%) and in atopic controls (C, 0.23 +/- 0.06%) than in eczema patients with low IgE (B, 0.42 +/- 0.19%) and non-atopic controls (D, 0.43 +/- 0.16%). There were no significant differences between groups for LIN, DGLA and AA, except for lower LIN levels in atopic controls. Correlation of individual LA and GLA values showed significantly steeper regression lines in low-IgE responders (B and D, k(x) = 0.058) than in high-IgE responders (A and C, k(x) = 0.012; p < 0.02), suggesting impaired delta-6-desaturase function in the latter. For the study population as a whole, there was a clear negative correlation between total levels of IgE and GLA (r(s) = -0.64) and a moderate negative correlation between total IgE and AA (r(s) = -0.38). CONCLUSIONS: Dysregulation of n-6 PUFA metabolism is neither consistently found in nor specifically associated with atopic dermatitis but rather appears to be associated with IgE production and atopy in general. The finding of decreased GLA levels in eczema patients with elevated total IgE and in children with allergic rhinitis and asthma but not in eczema patients with normal total IgE questions the proposed pathophysiologic role of fatty acid dysregulation in atopic dermatitis.

Asthma↗

PubMed2005

Choroidal neovascularization in pathologic myopia: three-year results after photodynamic therapy.

PURPOSE: To examine whether the encouraging functional results one year after photodynamic therapy (PDT) can be maintained up to three years. DESIGN: Prospective interventional case series. METHODS: Highly myopic eyes that had been treated with PDT for subfoveal choroidal neovascularization and had been observed at least 36 months were included. Distance acuity (Early Treatment of Diabetic Retinopathy charts), reading acuity (Jaeger charts), 10-degree static threshold perimetry, fluorescein angiography, and optical coherence tomography were performed. The main outcome measures were the differences of the values among the baseline and the month 12 and the month 36 examinations. RESULTS: Twenty eyes of 18 patients were included: 15 patients were female, and 3 patients were male. The average age was 64 years (range, 36 to 85 years). The mean distance acuity was 43 letters at baseline and 53 letters after 12 months and after 36 months. The mean reading acuity changed from mean J10.8 to mean J8.1 after 12 months and to mean J9.85 after 3 years. The mean defect decreased from mean 13.5 dB at baseline to mean 12.5 dB after 12 months and mean 11.2 dB after 36 months. The maximum retinal thickness decreased from mean 360 mum at baseline to mean 259 mum after one year and mean 238 mum after 36 months. CONCLUSION: Distance acuity and central visual field showed stabilization after the month 12 examination up to the month 36 examination. The reading acuity decreased between the month 12 and the month 36 examinations, which might be related to an increase of retinal atrophy.

Adult↗

PubMed2005

Adhesion, spreading, and aggregation of platelets in flowing blood and the reliability of the retention test Homburg.

Adhesion and aggregation are important parameters characterizing the function of intact platelets in flowing blood and in contact with a more or less thrombogenic surface. In the retention test Homburg (RTH), platelets are exposed to a standardized textured surface (Sysmex retention tubes) under defined conditions of flow. Platelet counts are performed before and after the Sysmex retention tube passage. The difference between these values indicates the percentage of retained platelets (retention index). Decreased retention in the RTH indicates a loss of function or defective platelet function; increase is associated with an increased activation of platelets, for example, in patients with vascular diseases. For further evaluation of the retention phenomenon the filters were fixed after cell passage and examined by scanning electron microscopy (SEM) and transmission electron microscopy (TEM). SEM and TEM micrographs show activated platelets adhering and spreading on the filter surface, comparable with platelets on a disturbed endothelium. Also, we examined the influence of different G forces and centrifugation times on the retention behavior of the platelets in citrated platelet-rich plasma (PRP) and whole blood (WB). G forces influenced the retention index in PRP and WB significantly and in a different way. Finally, we used a platelet standard, as customary in the quality check, to determine the serial as well as the day-to-day precision.

Biocompatible Materials↗

PubMed2005

Role of the retention test Homburg in evaluating platelet hyperactivity and in monitoring therapy with antiplatelet drugs.

Decreased retention in the retention test Homburg (RTH) indicates a loss of platelet function; increase is associated with an increased activation of platelets, for example, in patients with vascular diseases. Compared with other materials (e.g., collagen, glass pearls, etc.) the filter surface in the retention tubes is nonthrombogenic. Therefore, the RTH seems to be well suited for measuring an in vivo over-reactivity of platelets. In a pilot study using the RTH we evaluated the postoperative over-reactivity of platelets in 14 patients and observed a significant heterogeneity of the platelet population concerning size and stickiness. Reliable platelet function tests are also necessary for "drug monitoring," since they deliver important clinical laboratory parameters for efficient control of a therapy with antiplatelet drugs. Therefore, we evaluated in vitro how, after administration of platelet aggregation-inhibiting medications (such as acetylsalicylic acid, Prostaglandin and ReoPro in various concentrations, the adenosine diphosphate (ADP), collagen, ristocetin, or suprarenin increased retention can be reduced. The reaction of the platelets in platelet-rich plasma of different patients or donors to the addition of ADP is variable. The platelet function inhibitor effect is dose dependent. In a clinical pilot study, a significant platelet-inhibiting effect of clopidogrel using the RTH has been shown.

Abciximab↗

PubMed2004

The advantages and disadvantages of adaptive designs for clinical trials.

Flexible designs for clinical trials permit mid-trial design modifications, which are based on interim information from inside or outside the trial while meeting (regulatory) requirements for the control of the type I error rate. The basic principle is to combine stage standardized test statistics such as p-values or z-scores in a pre-specified way. The flexibility covers changes of sample sizes, treatment allocation ratios and the number of interim analyses, as well as the selection of treatments, doses and end points. The price to be paid is that non-standard test statistics must be used after an adaptation.

Biomedical Research↗

PubMed2004

Predictors of mortality at initiation of peritoneal dialysis in children after cardiac surgery.

BACKGROUND: The development of renal dysfunction in the postoperative course of cardiac surgery is still associated with high mortality in pediatric patients. In particular for small infants peritoneal dialysis offers a secure and useful treatment option. The aim of the present study was to investigate if routinely used laboratory and clinical variables could help predict mortality at initiation of peritoneal dialysis. METHODS: We performed a retrospective chart analysis of pediatric intensive care unit patients with renal dysfunction who were treated with peritoneal dialysis after cardiac surgery between 1993 and 2001 and analyzed variables obtained 3 hours or less before starting peritoneal dialysis. RESULTS: Results are documented as means and standard errors. A total of 1141 children underwent a cardiac operation on cardiopulmonary bypass. Sixty-two children (5.4%) were treated with peritoneal dialysis. Mortality was 40.3% (37 survivors, 25 nonsurvivors). The pH in survivors was 7.35 (0.01); in nonsurvivors it was 7.23 (0.03; p = 0.0037). Base excess in survivors was -1.37 mmol/L (0.61); in nonsurvivors it was -7.17 mmol/L (1.49; p = 0.0026). Lactate in survivors was 4.5 mmol/L (0.60); in nonsurvivors it was 10.5 mmol/L (1.78; p = 0.0089). Positive inspiratory pressure in survivors was 24.6 cm H(2)O (0.78); in nonsurvivors it was 28.9 cm H(2)O (1.08; p = 0.0274). Tidal volume per kilogram bodyweight in survivors was 11.0 mL/kg (0.48); in nonsurvivors it was 8.7 mL/kg (0.50; p = 0.0493). CONCLUSIONS: We conclude from our data that the consideration of pH, base excess, lactate, positive inspiratory pressure, and tidal volume per kilogram bodyweight help predict mortality at initiation of peritoneal dialysis. We were able to observe significant differences between survivors and nonsurvivors using these variables.

Cardiac Surgical Procedures↗

PubMed2004

Optimal conditional error functions for the control of conditional power.

Ethical considerations and the competitive environment of clinical trials usually require that any given trial have sufficient power to detect a treatment advance. If at an interim analysis the available data are used to decide whether the trial is promising enough to be continued, investigators and sponsors often wish to have a high conditional power, which is the probability to reject the null hypothesis given the interim data and the alternative of interest. Under this requirement a design with interim sample size recalculation, which keeps the overall and conditional power at a prespecified value and preserves the overall type I error rate, is a reasonable alternative to a classical group sequential design, in which the conditional power is often too small. In this article two-stage designs with control of overall and conditional power are constructed that minimize the expected sample size, either for a simple point alternative or for a random mixture of alternatives given by a prior density for the efficacy parameter. The presented optimality result applies to trials with and without an interim hypothesis test; in addition, one can account for constraints such as a minimal sample size for the second stage. The optimal designs will be illustrated with an example, and will be compared to the frequently considered method of using the conditional type I error level of a group sequential design.

Biometry↗

PubMed2003

Issues in designing flexible trials.

We outline the general framework of adaptive combination tests and discuss their relationship to flexible group sequential designs. An important field of applications is sample size reassessment. We discuss reassessment rules based on conditional power arguments using either the observed or the prefixed effect size. These rules tend to lead to large expected sample sizes for small actual effects. However, the application of a maximal bound for the second stage sample size leads to more favourable properties. Additionally, we consider an optimized reassessment rule in terms of expected sample sizes. Since the adaptive design does not use the classical test statistics for some types of sample size reassessments, the adaptive test may reject the null hypothesis while the classical one-sample test does not. We characterize sample size reassessment rules, where such inconsistencies are avoided. Finally, the extension of flexibility to the number of stages is explored. In the first interim analysis a second interim analysis is only planned if the chance to achieve a decision there is high. This leads to savings in the average number of interim analysis performed, without paying a noticeable price in terms of expected sample size.

Clinical Trials as Topic↗

PubMed2003

Impaired gastric emptying and altered intragastric meal distribution in diabetes mellitus related to autonomic neuropathy?

Previous studies in diabetic patients suggested a relationship between delayed gastric emptying and increased ingesta retention in either proximal or distal stomach, but the determinants underlying these abnormalities remained obscure. We aimed at assessing the impact of cardiovascular autonomic neuropathy, blood glucose concentration, long-term glycemic control, and other factors in 34 type I and 43 type II diabetic patients (ages 21-67 and 34-81 years, respectively). Emptying was slower (P < 0.04) in type I diabetic patients than in 20 healthy control subjects (ages 23-63 years). Patients with autonomic neuropathy (N = 45) had slower gastric emptying (P < 0.02) and retained more in the distal stomach (P < 0.0001) than patients without neuropathy (N = 32). Multiple regression analyses revealed that slow emptying and increased distal retention were significantly associated with autonomic neuropathy (P < 0.043, P < 0.0002), whereas blood glucose, glycemic control, diabetes duration, age, and other factors had no discernible influence. Thus, both slow emptying and increased distal ingesta retention seem primarily referable to autonomic neuropathy.

Adult↗