Biomedical subjects

Hans-Helge Müller

Publications and source records attributed to Hans-Helge Müller.

18 recordsLinked to original sources

PubMed2007

Increasing the sample size during clinical trials with t-distributed test statistics without inflating the type I error rate.

In clinical trials with t-distributed test statistics the required sample size depends on the unknown variance. Taking estimates from previous studies often leads to a misspecification of the true value of the variance. Hence, re-estimation of the variance based on the collected data and re-calculation of the required sample size is attractive. We present a flexible method for extensions of fixed sample or group-sequential trials with t-distributed test statistics. The method can be applied at any time during the course of the trial and does not require the necessity to pre-specify a sample size re-calculation rule. All available information can be used to determine the new sample size. The advantage of our method when compared with other adaptive methods is maintenance of the efficient t-test design when no extensions are actually made. We show that the type I error rate is preserved.

Computer Simulation↗

PubMed2006

An overview of statistical approaches for adaptive designs and design modifications.

With adaptive design methods for clinical trials, design elements such as sample size or further interim sample sizes may be changed during the course of the trial depending on all previously collected data. The focus of the overview is on group sequential approaches where the types of adaptations need not be specified in advance. An overview of the different statistical approaches for adaptive design methods proposed in the literature is given, relations between these methods are described and some perspectives of application and for future research are discussed.

Clinical Trials as Topic↗

PubMed2006

IgG reactivity against non-conformational NH-terminal epitopes of the desmoglein 3 ectodomain relates to clinical activity and phenotype of pemphigus vulgaris.

Pemphigus vulgaris (PV) is an autoimmune disease caused by immunoglobulin G (IgG) autoantibodies against the desmosomal adhesion molecules, desmoglein (Dsg)3 and Dsg1. The aim of the study was to relate IgG reactivity of 123 PV sera and 40 control sera against NH(2)-terminal non-conformational epitopes of Dsg3 and Dsg1 with disease activity and clinical phenotype by enzyme-linked immunosorbent assay. The results show that (i) the overall reactivity and the titres of IgG reactive with the Dsg3 ectodomain, Dsg3(1-566), significantly correlated with the disease activity of the PV patients; (ii) IgG reactivity against the NH(2)-terminus of Dsg3, Dsg3(1-161), was associated with active PV while there was no direct correlation between the IgG titres and the disease activity; (iii) IgG reactivity against the NH(2)-terminus of Dsg3, Dsg3(1-161), was associated with mucosal and mucocutaneous PV; (iv) IgG titres against a small stretch of the NH(2)-terminus of Dsg3, Dsg3(25-88), were associated with active PV; and (v) IgG in the PV sera detected non-conformational epitopes in addition to the previously identified conformation-dependent epitopes of the Dsg3 and Dsg1 ectodomains.

Baculoviridae↗

PubMed2005

Predictive value of electrocorticography in epilepsy patients with unilateral hippocampal sclerosis undergoing selective amygdalohippocampectomy.

The purpose of this study was to evaluate the predictive value of intraoperative electro-corticography (ECoG) in patients with unilateral hippocampal sclerosis (HS) undergoing transsylvian selective amygdalohippocampectomy (sAHE). ECoG was recorded before and after resection in 22 patients with medication-resistant mesial temporal lobe epilepsy. The sAHE was performed, regardless of ECoG findings. ECoG findings recorded from the mesiobasal temporal lobe (MTL) and lateral temporal lobe (LTL) before and after the sAHE were correlated with seizure outcome 12 months later. Ten patients had right-sided and 12 left-sided HS. Average age was 37.1 years. Pre-resection spikes were restricted to the MTL in 11 patients and to the LTL in one. In three patients spikes were recorded from MTL and LTL and in seven no spikes were recorded before the resection. Fifteen patients (68%) remained completely seizure-free and 19 (86%) were in Engel's class I post-operatively. Patients with pre-resection spikes restricted to the MTL (n = 11) remained seizure-free more frequently (9/11, 82%) compared with other patients (6/11, 55%; P = 0.36). Pre-resection ECoG may be helpful in the prediction of seizure outcome in patients undergoing sAHE for mesial temporal lobe epilepsy. A larger study including more than 100 patients is needed to determine the predictive value of ECoG in patients with mesial temporal lobe epilepsy.

Adolescent↗

PubMed2005

Octreotide versus octreotide plus interferon-alpha in endocrine gastroenteropancreatic tumors: a randomized trial.

BACKGROUND & AIMS: The effect of octreotide plus interferon-alpha versus octreotide monotherapy on the primary study end points of time to treatment failure (progression, death, stop of study treatment) and long-term survival was investigated in patients with progressive metastatic neuroendocrine foregut (mainly pancreatic) and midgut tumors. METHODS: One hundred nine of 125 registered patients were randomized starting in January 1995, and 105 patients (51 monotherapy, 54 combination treatment) were finally analyzed in March 2000. Tumor growth was assessed at 3-month intervals by computed tomography or magnetic resonance imaging. Long-term survival was studied up to April 2004 in all analyzed patients and in 9 patients not randomized because of stable disease. RESULTS: Partial tumor regression occurred in 2.9%, 1.9%, and 5.7% and stabilization of tumor growth in 44.8%, 27.6%, and 15.2% at 3, 6, and 12 months, respectively, with no significant differences between both treatment arms. In March 2000, 9.5% of patients were in treatment. Time to treatment failure and long-term survival did not differ significantly between the 2 groups, with a median survival of 32 and 54 months for the octreotide and the combination groups, respectively. Survival was longer in patients not randomized because of stable disease (median, 68 months) and in those with low nuclear Ki-67. A trend toward longer survival was shown for patients with slow spontaneous tumor growth before randomization. Patients responding to treatment lived longer than unresponsive patients. CONCLUSIONS: Combination treatment was not superior to monotherapy concerning progression-free and long-term survival. Patients responding to treatment and those with slow spontaneous tumor growth had a survival advantage.

Adolescent↗

PubMed2005

[Long-term benefits of a postgraduate programme in clinical epidemiology. The study programme "clinical evaluation" of the University of Marburg].

In 1997 the first Clinical Epidemiology Programme in Germany was founded at the University of Marburg. This has been a part-time programme of six months' duration for young medical researchers interested in study planning, conduct and analysis. We report the results of focus group evaluations undertaken at the end of each programme which is held every year. We also surveyed former participants by phone to assess long-term effects of the programme. Overall, according to participants' feedback the programme has been a success. In particular, competences in study planning and critical appraisal were considered useful. However, participants reported difficulties implementing their newly gained knowledge and skills within their home departments. Postgraduate programmes of this kind catalyze the establishment of clinical research at German University Medical Centres.

Education, Medical, Graduate↗

PubMed2004

A general statistical principle for changing a design any time during the course of a trial.

A general method is presented that allows the researcher to change statistical design elements such as the residual sample size during the course of an experiment, to include an interim analysis for early stopping when no formal rule for early stopping was foreseen, to increase or reduce the number of planned interim analyses, to change time points and the type I error spending function for the further design of interim analyses, or to change the test statistic, the outcome measure, etc. At the time of a pre-planned interim analysis for early stopping or at any time of an interim look without spending part of the type I error level the method offers the option to completely redesign the remaining part of the trial, without affecting the type I error level. The method is described in the usual Brownian motion model and extended to the general context of statistical decision functions. It is based on the conditional rejection probability of a decision variable.

Antiparkinson Agents↗

PubMed2004

Construction of group sequential designs in clinical trials on the basis of detectable treatment differences.

The treatment effect sizes that can be detected with sufficient power up to the different interim analyses constitute a clinically meaningful criterion for the selection of a group sequential test for a clinical trial. For any pre-specified sequence of effect sizes, it is possible to construct group sequential boundaries such that the trial has a pre-specified power to reject the null-hypothesis at or before the corresponding interim analysis under the respective treatment effect. The principle of constructing group sequential designs on the basis of detectable treatment effects is presented. The application in common situations such as two-armed trials with continuous or binary outcome or censored survival times is described. We also present an effective algorithm.

Algorithms↗

PubMed2003

Noninvasive arrhythmia risk stratification in idiopathic dilated cardiomyopathy: results of the Marburg Cardiomyopathy Study.

BACKGROUND: Arrhythmia risk stratification with regard to prophylactic implantable cardioverter-defibrillator therapy is a completely unsolved issue in idiopathic dilated cardiomyopathy (IDC). METHODS AND RESULTS: Arrhythmia risk stratification was performed prospectively in 343 patients with IDC, including analysis of left ventricular (LV) ejection fraction and size by echocardiography, signal-averaged ECG, arrhythmias on Holter ECG, QTc dispersion, heart rate variability, baroreflex sensitivity, and microvolt T-wave alternans. During 52+/-21 months of follow-up, major arrhythmic events, defined as sustained ventricular tachycardia, ventricular fibrillation, or sudden death, occurred in 46 patients (13%). On multivariate analysis, LV ejection fraction was the only significant arrhythmia risk predictor in patients with sinus rhythm, with a relative risk of 2.3 per 10% decrease of ejection fraction (95% CI, 1.5 to 3.3; P=0.0001). Nonsustained ventricular tachycardia on Holter was associated with a trend toward higher arrhythmia risk (RR, 1.7; 95% CI, 0.9 to 3.3; P=0.11), whereas beta-blocker therapy was associated with a trend toward lower arrhythmia risk (RR, 0.6; 95% CI, 0.3 to 1.2; P=0.13). In patients with atrial fibrillation, multivariate Cox analysis also identified LV ejection fraction and absence of beta-blocker therapy as the only significant arrhythmia risk predictors. CONCLUSIONS: Reduced LV ejection fraction and lack of beta-blocker use are important arrhythmia risk predictors in IDC, whereas signal-averaged ECG, baroreflex sensitivity, heart rate variability, and T-wave alternans do not seem to be helpful for arrhythmia risk stratification. These findings have important implications for the design of future studies evaluating prophylactic implantable cardioverter-defibrillator therapy in IDC.

Adolescent↗

PubMed2003

Reducing sample sizes in genome scans: group sequential study designs with futility stops.

Group sequential study designs can greatly facilitate analyses of genetic linkage in complex traits. We recently proposed designs allowing stopping investigations early if the result is significant (König et al. [2001] Am. J. Hum. Genet. 69:590-600), thereby decreasing average sample sizes under the alternative hypothesis. However, average sample sizes were slightly increased under the null hypothesis. We now present designs where the analysis of markers is additionally stopped in case of futility, i.e., if the probability for significant results is sufficiently low. These sequential designs are applied to linkage analyses of single loci. We calculated sample sizes, time points, and critical boundaries for all analyses for 2- and 3-stage designs at an overall significance level of 0.0001. To confirm the validity of asymptotic approximations, Monte Carlo simulations were performed. The utility is demonstrated analyzing genome scan data provided for the Genetic Analysis Workshop 12. Application of the novel sequential designs yields tremendous decreases in average sample sizes, regardless of the size of the underlying genetic effect at investigated loci. Depending on the applied design, almost half of the sample size is spared on average. These enormous savings are expected to have a special impact on costs and time of large-scale studies such as genome scans.

Genetic Linkage↗

PubMed2003

Value of heart rate variability to predict ventricular arrhythmias in recipients of prophylactic defibrillators with idiopathic dilated cardiomyopathy.

This study investigated the relation between heart rate variability (HRV) measured as standard deviation of normal to normal RR intervals (SDNN) on baseline 24-hour ambulatory electrocardiogram (ECG) and subsequent appropriate implantable cardioverter defibrillator (ICD) interventions in 70 patients with idiopathic dilated cardiomyopathy (IDC) in whom ICDs were implanted prophylactically in the presence of a low left ventricular ejection fraction (LVEF). During 43 +/- 26 months of follow-up, 26 of 70 (37%) study patients with IDC received one or more appropriate ICD interventions for sustained ventricular tachycardia (VT) or ventricular fibrillation (VF) documented by electrograms stored in the ICD. Mean SDNN at ICD implant was 94 +/- 33 ms. No difference was found between patients with (90 +/- 25 ms) versus without (96 +/- 37 ms) appropriate ICD interventions for VT or VF during follow-up. Multivariate Cox regression analysis of baseline clinical characteristics including age, gender, LVEF, NYHA functional class, nonsustained VT on Holter, history of syncope, left bundle branch block, baseline medication and HRV revealed LVEF as the only significant predictor of arrhythmia. These findings do not support the use of HRV measured as SDNN on 24-hour ambulatory ECG to select patients with IDC for prophylactic ICD therapy.

Cardiomyopathy, Dilated↗

PubMed2003

Prognostic significance of heart rate turbulence following ventricular premature beats in patients with idiopathic dilated cardiomyopathy.

UNLABELLED: Heart Rate Turbulence in Dilated Cardiomyopathy. INTRODUCTION: The aim of this study was to investigate the prognostic significance of heart rate turbulence (HRT) characterized by HRT onset and slope after ventricular premature beats in patients with idiopathic dilated cardiomyopathy (IDC). METHODS AND RESULTS: Blinded HRT analysis was performed in 242 patients with IDC who were enrolled in the Marburg Cardiomyopathy database between 1992 and 2000. During 41 +/- 23 months of follow-up, 54 patients (22%) died or underwent heart transplant. On Cox univariate regression analysis, abnormal HRT onset, HRT slope, HRT onset combined with HRT slope, left ventricular (LV) ejection fraction, LV size, and New York Heart Association (NYHA) functional class III showed a significant association with total mortality or the need for heart transplant. On multivariate analysis, abnormal HRT onset identified patients without transplant-free survival, as did LV size and NYHA class III heart failure. Major arrhythmic events were observed in 42 patients (17%) during follow-up. On univariate analysis, abnormal HRT onset, HRT onset combined with HRT slope, male sex, NYHA class III, LV ejection fraction, and LV size were associated with a higher incidence of major arrhythmic events. On multivariate analysis, only LV ejection fraction remained as a significant arrhythmia risk predictor, with a relative risk of 2.2 per 10% decrease in ejection fraction (95% confidence interval 1.5-3.2). CONCLUSION: In this selected patient population with IDC, HRT onset is a significant predictor of transplant-free survival, as are LV size and NYHA class. For arrhythmia risk stratification, however, only LV ejection fraction remained a significant risk predictor on multivariate analysis.

Age Distribution↗

PubMed2003

Prevalence of potential noninvasive arrhythmia risk predictors in healthy, middle-aged persons.

BACKGROUND: To date, prevalence and clinical significance of noninvasive arrhythmia risk predictors in apparently healthy, middle-aged persons are largely unknown. METHODS: A total of 110 apparently healthy persons 20-75 years old were enrolled in this prospective observational monocenter study and followed up for 32 +/- 15 months. Baseline investigations included symptom-limited bicycle ergometry, echocardiography, time-domain analysis, and spectral turbulence analysis of the signal-averaged electrocardiogram (ECG), ventricular arrhythmias, and heart rate variability on 24-hour Holter ECG, baroreflex sensitivity, and t-wave alternans in all persons. RESULTS: The prevalence of an abnormal signal-averaged ECG was 1% for spectral turbulence analysis and varied between 1% and 37% for time-domain analysis depending upon the definition used for an abnormal time-domain analysis. A reduced heart rate variability defined as a standard deviation of normal-to-normal intervals < or =105 ms, <100 ms and <70 ms was found in 12%, 9%, and 1% of persons. A baroreflex sensitivity <6 ms/mmHg and <3 ms/mmHg was present in 15% and 2% of persons. Microvolt t-wave alternans was found to be positive in 5%, negative in 88%, and indeterminate in 7% of persons, respectively. During the 32 +/- 15 months follow-up, no arrhythmic events and no cardiovascular mortality were observed in this population. CONCLUSIONS: Abnormal findings of noninvasive arrhythmia risk stratification can be found in 1-37% of healthy, middle-aged persons when previously reported cut-off values are used.

Adult↗

PubMed2003

Technical complications of continuous intra-arterial chemotherapy with 5-fluorodeoxyuridine and 5-fluorouracil for colorectal liver metastases.

BACKGROUND: Intra-arterial chemotherapy is an effective modality to treat unresectable hepatic metastases from colorectal primaries if systemic chemotherapy has failed. Response rates of more than 40% and a median survival of 15 to 25 months have been reported from randomized trials. In this retrospective study, we analyzed specific technical complications associated with continuous intra-arterial chemotherapy for colorectal liver metastases. METHODS: From 1982 to 1995, single-center clinical data from 180 patients with colorectal liver metastases were evaluated. Continuous intra-arterial chemotherapy was administered using either an implanted infusion pump or an intra-arterial port with an external infusion pump. The intra-arterial catheter was implanted according to the Watkins' technique. The treatment protocols consisted of 5-fluorouracil- or 5-fluorodeoxyuridine-based regimens. RESULTS: A total of 70 patients (39%) received an intra-arterial infusion pump and 110 patients (61%) an intra-arterial port. Sixty-eight technical complications affected port systems (62%), whereas 29 patients with pumps (41%) were affected by technical complications. Therapy-relevant complications were observed in 47% of the ports and 30% of the infusion pumps. The median complication-free survival was 12.2 months for infusion pumps and 7.3 months for ports (P =.0016). CONCLUSIONS: Our data demonstrate that pumps are superior to ports in terms of complication rate and complication-free survival. On the basis of our results, pumps have a potential for a longer treatment, which may result in a prolonged median survival.

Antimetabolites, Antineoplastic↗

PubMed2003

The German multicenter, randomized, partially blinded, prospective trial of acupuncture for chronic low-back pain: a preliminary report on the rationale and design of the trial.

BACKGROUND: The efficacy of acupuncture treatment for chronic low-back pain has not been reliably proven because of a lack of good quality studies, leading to the necessity of developing the German Acupuncture Trial for Chronic Low-Back Pain (GERAC-cLBP) study. OBJECTIVE: The aim is to assess the effectiveness of traditional Chinese acupuncture for chronic low-back pain compared to sham acupuncture and with a conventional standard therapy. METHODS: This trial is a nationwide, multicenter, randomized, prospective, partially blinded study. The primary endpoint is the success rate after 6 months. Success is defined as an improvement of 33% or more of three pain-related items on the Van-Korff Pain Score or an improvement of 12% or more in the disability measured by the Hanover Functional Ability Questionnaire. Assessment of the effectiveness of the blinding of patients to the form of acupuncture they received will be conducted. All clinical endpoints are assessed centrally by blinded independent observers. The sample size, with a total of 1062 patients to be enrolled, is based on power calculations. Independent central randomization, data collection, data processing, and statistical analysis are provided. Success rates will be tested for differences using two-sided Fisher exact tests. In the primary analysis, all tests will be carried out on the basis of the intention-to-treat principle. Secondary analyses will be conducted according to protocol approaches. TRIAL STATUS: The pilot phase of the trial started in February 2002, the estimated duration of the study is 2.5 years. Enrollment is anticipated to be completed in the winter of 2003. CONCLUSION: The GERAC-cLBP study is currently the world's largest controlled trial of the effectiveness of acupuncture treatment for low-back pain. It will contribute to the evaluation of efficacy by means of evidence based medicine.

Acupuncture Therapy↗

PubMed2003

Data adaptive interim modification of sample sizes for candidate-gene association studies.

OBJECTIVES: The use of conventional Transmission/Disequilibrium tests in the analysis of candidate-gene association studies requires the precise and complete pre-specification of the total number of trios to be sampled to obtain sufficient power at a certain significance level (type I error risk). In most of these studies, very little information about the genetic effect size will be available beforehand and thus it will be difficult to calculate a reasonable sample size. One would therefore wish to reassess the sample size during the course of a study. METHOD: We propose an adaptive group sequential procedure which allows for both early stopping of the study with rejection of the null hypothesis (H0) and for recalculation of the sample size based on interim effect size estimates when H0 cannot be rejected. The applicability of the method which was developed by Müller and Schäfer [Biometrics 2001;57:886-891] in a clinical context is demonstrated by a numerical example. Monte Carlo simulations are performed comparing the adaptive procedure with a fixed sample and a conventional group sequential design. RESULTS: The main advantage of the adaptive procedure is its flexibility to allow for design changes in order to achieve a stabilized power characteristic while controlling the overall type I error and using the information already collected. CONCLUSIONS: Given these advantages, the procedure is a promising alternative to traditional designs.

Data Interpretation, Statistical↗

PubMed2002

[The effectiveness of radiation treatment in comparison with extracorporeal shockwave therapy (ESWT) in supraspinatus tendon syndrome].

BACKGROUND AND AIM: Supraspinatus tendinitis is usually treated by antiinflammatoric drugs, local injections, physiotherapy or low-dose irradiation. A novel approach is the use of Extracorporeal Shock Wave Therapy (ESWT) if conservative therapies have failed. So far there has been no controlled study comparing the effectiveness of ESWT with an established conservative method of therapy such as X-ray stimulation radiotherapy. PATIENTS AND METHOD: 30 patients with chronic supraspinatus tendinitis were admitted into the prospective randomized study. After randomization the patients were treated either with X-ray stimulation radiotherapy with 6 x 0.5 Gy on the ICRU reference point (1 fraction/day) with cobalt 60 gamma rays or three times with 2000 pulses (energy flux density ED+ 0.1 mJ/mm2) in 1 week intervals using a Storz Minilith SL1. Primary endpoint was the age-corrected constant score 3 months after intervention. RESULTS: Acute side effects caused by the irradiation were not observed, as expected. One patient described pain and one patient showed a moderate skin irritation after ESWT. In the radiotherapy group average the age-corrected constant score improved from 47.6 through 79.5 points to 87.4 points. In the ESWT group it rose from 50.1 points before ESWT to 91.4 points after 12 weeks and 97.8 after 52 weeks. CONCLUSION: No statistically significant differences were proven between ESWT and radiotherapy. ESWT appears to be equivalent but not superior to radiotherapy in treating chronic supraspinatus tendinitis syndrome. A comprehensive randomized study is, however, necessary to ensure the equivalence of ESWT.

Adult↗

PubMed2002

Topiramate selectively decreases intracortical excitability in human motor cortex.

PURPOSE: Topiramate (TPM) is a novel drug with broad antiepileptic effect in children and adults. In vitro studies suggest activity as sodium-channel blocker, as gamma-aminobutyric acid type A (GABAA)-receptor agonist and as non-N-methyl-D-aspartate (NMDA)-glutamate receptor antagonist. METHODS: With transcranial magnetic stimulation (TMS), we evaluated which of the mechanisms of action of TPM detected in vitro are relevant for the modulation of human motor cortex excitability. In a double-blind, placebo-controlled, crossover study design, we investigated the effect of single oral doses of 50 mg and 200 mg TPM on motor thresholds, cortical silent period (CSP), and on intracortical inhibition (ICI) and intracortical facilitation (ICF) in 20 healthy subjects. RESULTS: A significant dose-dependent increase of ICI was noticed after 200 mg TPM as compared with placebo at short interstimulus intervals of 2 to 4 ms. TPM had no effect on motor thresholds or the CSP. CONCLUSIONS: We conclude that a single dose of TPM selectively increases ICI by GABAAergic and/or glutamatergic mechanisms without a relevant influence on measures, depending on ion-channel blockade or GABAB-receptor activity. The decrease of intracortical excitability (as measured by ICI and ICF) caused by TPM may correlate with its lack of proconvulsive potential in idiopathic generalized epilepsy, because drugs without this action or with less pronounced action may exacerbate seizures in this condition.

Adult↗