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S Wellek

Publications and source records attributed to S Wellek.

At least 19 recordsLinked to original sources
PubMed2005

A new approach to sample size calculation for reference interval studies.

A new criterion is proposed for determining the sample size required for a study performed for the purpose of establishing reference intervals. The basic idea behind the criterion is to compare the empirical coverage (i.e. the probability content) of the reference region obtained from the sample with its target value (e.g. 95 per cent) and to set suitable limits delta1, delta2 to the difference between both quantities which must not be exceeded with sufficiently large probability beta (e.g. beta=90 per cent). For the most frequently used parametric and distribution-free methods of estimating univariate reference limits, implicit formulae are derived relating the sample size to the design parameters delta1, delta2 and beta. For symmetric specification of (delta1, delta2), explicit approximation formulae for the computation of n are given. Exact values obtained by means of suitable numerical techniques are presented in a set of tables covering specifications of delta1, delta2 and beta which can be recommended for real applications. The tables can be used both for one- and two-sided reference intervals.

Alanine Transaminase↗
PubMed2004

Statistical confirmation of negative results of association studies in genetic epidemiology.

One of the most important reasons warranting the common reservation about publishing association studies with negative results is due to the fundamental fact that an insignificant result of a statistical testing procedure tailored for establishing an association, fails to provide conclusive evidence of the contrary. In this contribution, we show how the methodology of equivalence testing, as provided by modern biostatistics, can be exploited for removing this basic flaw. In order to keep the exposition as simple as possible, we restrict discussion to the setting of a study which aims at ruling out that some given single SNP has a relevant impact on the risk of developing the disease under consideration. As solutions to the problem of how to perform a valid confirmatory analysis of a trial of this type, two different approaches are presented: (i) exact Fisher type test for equivalence of an odds ratio to unity; (ii) distribution-free test for equivalence of cases and controls with respect to the full (i.e., trinomial) genotype distributions. The practical implementation of both testing procedures are described in detail and illustrated with examples taken from recent studies of the genetic epidemiology of psychiatric disorders.

Case-Control Studies↗
PubMed2002

Relationship between cortisol and serotonin metabolites and transporters in alcoholism [correction of alcolholism].

BACKGROUND: Stress hormone activation may induce clinical depression via an interference with central serotonergic neurotransmission. In alcoholics, a reduction in serotonin transporters was associated with clinical depression, and an activation of cortisol secretion is frequently found during detoxification. We assessed the interaction between stress hormone activation, serotonin transporters, monoamine metabolites in the cerebrospinal fluid (CSF), and mood states in male and female alcoholics and healthy control subjects. METHODS: The availability of serotonin transporters was measured with [I-123]beta-CIT and SPECT in the raphe area of the brainstem in 31 alcoholics after four weeks of abstinence and in 25 age-matched healthy volunteers. Concentrations of plasma cortisol were measured on the day of the SPECT scan. Within one week after the SPECT scan, we assessed monoamine metabolites and corticotropin-releasing factor (CRF) in the CSF. RESULTS: Clinical depression was associated with a reduction in serotonin transporter availability among male alcoholics. Among male alcoholics and healthy volunteers, CSF 5-HIAA and plasma cortisol concentrations were inversely correlated with the availability of raphe serotonin transporters and positively correlated with the severity of clinical depression. No significant correlations were observed between raphe serotonin transporters and HVA, MHPG and CRF concentrations in the CSF. CONCLUSION: Our findings support the hypothesis of an interaction between reduced serotonin transporters, stress hormone activation and clinical depression. They confirm the hypothesis that serotonergic neurotransmission dysfunction in alcoholism is limited to male alcoholics. The observed interactions between high cortisol concentrations and reduced serotonin transporter availability warrant further studies in major depression and other neuropsychiatric diseases with implied cortisol activation and serotonergic dysfunction.

Adult↗
PubMed2001

Reference values of fetal aortic flow velocity waveforms and associated intra-observer reliability in normal pregnancies.

OBJECTIVES: It was the aim of the present study to calculate new Doppler reference ranges for blood flow velocities (Vmax, Vmean, Vmin) and resistance indices (PI, RI) for the fetal descending aorta by automatic waveform analysis. DESIGN: Cross-sectional prospective study. SUBJECTS: Nine hundred and twenty-six low-risk pregnancies at 18-41 weeks' gestation. METHODS: Aortic blood flow velocities were derived with pulsed-wave color Doppler. Measurements were carried out at the level of the diaphragm. Reference ranges for the individual measuring parameters were constructed based on a growth function from a four-parameter class of monotonic continuous functions according to the smallest square principle. Further investigated were intra-observer reliability and the influence exerted by different measuring sites (aortic arch, diaphragm, below the renal vessels) on the aortic Doppler flow spectrum. RESULTS: Although a significant increase in aortic blood flow velocity was observed at 18-41 weeks' gestation (Vmax = 48.2 cm/s to 110.3 cm/s (P < 0.001), Vmean = 20 cm/s to 47.5 cm/s (P < 0.001) and Vmin = 7.6 cm/s to 18.6 cm/s (P < 0.001)), there were no significant changes in the pulsatility or resistance indices. The resistance indices PI and RI as well as absolute blood flow velocities (Vmax, Vmin) were significantly lower with increasing distance from the heart. Initial decreases were measured between the aortic arch and the diaphragm: PI, 2.34 to 1.87 (P < 0.0001); RI, 0.87 to 0.79 (P < 0.0001); Vmin: 8.5 cm/s to 15.0 cm/s (P < 0.0001). Furthermore, systolic blood flow velocities (Vmax) were decreased below the renal vessels from 97 cm/s to 64 cm/s (P < 0.0007). No significant changes were recorded in intensity-weighted mean flow velocities (Vmean). The intra-observer reliability was low, but of no clinical relevance. CONCLUSIONS: At constant measuring conditions, the reference ranges for blood flow velocities and resistance indices in the fetal aorta calculated by the authors serve as the basis for Doppler ultrasound antenatal examinations in a normal patient population and enable the early diagnosis of fetal risk.

Aorta, Thoracic↗
PubMed2001

Age-related reference regions for longitudinal measurements of growth characteristics.

Most studies on age-related reference centiles published up to now have adopted a strictly cross-sectional perspective. Clearly, the results of studies of that type do not provide a tool for the diagnostic assessment of whole series of measurements taken sequentially over time in the same individual. In this paper, the approach of Wellek & Merz (1995) to the construction of age-dependent reference ranges for cross-sectional measurements is generalized in such a way that data sets containing time series of arbitrary length varying between subjects can be accommodated. Since repeated measurements on the same subject are typically correlated, the regression function to be used as the central line for the reference band eventually obtained is determined by fitting a nonlinear mixed model describing the dependence of conditional means on age by growth functions of the same class we proposed in the case of cross-sectional data. Estimation of the parameters of this mixed model is done in a way closely related to the population-averaged GEE approach by Zeger et al. (1988). Given the regression line, the reference band is constructed by means of an iterative procedure guaranteeing that the proportion of observed profiles which nowhere leave the band, has some prespecified value (frequently set equal to 90% in practice). The approach is illustrated with two examples taken from child psychiatry and prenatal sonography.

Adolescent↗
PubMed2000

On a reasonable disaggregate criterion of population bioequivalence admitting of resampling-free testing procedures.

The aggregate criterion of population bioequivalence (PBE) recommended in the new FDA guidance for in vivo bioavailability studies is criticized for using the same distributional parameter as a reference for scaling the squared distance between the averages and the difference in variability. In order to circumvent this and other difficulties inherent in the approach to PBE having been recommended thus far, we introduce a disaggregate criterion instead which requires of population bioequivalent drug formulations that both the difference in means scaled by the pooled intrasubject standard deviation be sufficiently small in absolute value, and the total variability be not substantially increased under the test as compared to the reference formulation. For testing the first of the statistical hypotheses associated with this combined criterion, an exact optimal procedure based on the ordinary two-sample t-statistic is presented. As a test for equivalence with respect to total variability, a modification of Liu and Chow's one-sided test procedure for the assessment of intrasubject variability is recommended. Both subtests are combined by means of the intersection-union principle explained here in general terms, to form an overall test for disaggregate PBE maintaining any specified significance level. The power of the combined procedure is investigated by means of Monte Carlo simulation.

Area Under Curve↗
PubMed2000

Long term follow-up of combined radiochemotherapy for locally advanced bladder carcinoma.

BACKGROUND: The 5- and 10-year survival rates and the toxicity of combined radiochemotherapy for 53 consecutive patients with locally advanced bladder carcinoma were studied in a noncomparative trial. METHODS: Between November 1986 and October 1987, 53 consecutive patients (mean age, 68 years) with muscle invasive and/or locally advanced bladder carcinoma were treated by simultaneous chemotherapy and hyperfractionated irradiation. Radiation was administered during the first to fourth week and during the ninth to tenth week as an interrupted treatment protocol. Cisplatin and epirubicin were used as radiosensitizers before radiation. The maximum dose of irradiation was 57.6 grays. RESULTS: Of 53 patients, 45 completed the planned treatment course. Causes for discontinuing therapy in 8 patients were pronounced myelosuppression (n = 2), severe gastrointestinal symptoms (n = 2), nephrotoxicity (n = 1), and severe radioproctitis (n = 1). Two additional patients stopped therapy due to vascular diseases independent of treatment-related toxicity. The overall survival for all 53 patients was 23% after 5 years and 8% after 10 years. Cause specific survival was 36% after 5 years and 29% after 10 years. Four patients are still alive after 10 years without disease progression. One of them received incomplete therapy due to toxicity. All four patients underwent transurethral resections for superficial, local tumor recurrences. CONCLUSIONS: The poor prognosis group of patients with invasive and/or locally advanced bladder carcinoma was found to have a limited disease specific survival after combined radiochemotherapy.

Adult↗
PubMed2000

[Proof of equivalence as a new issue in confirmatory statistics].

A correct confirmatory analysis of studies aiming at demonstration of equivalence requires the use of a class of testing procedures that is still widely unknown among non-specialists and not even mentioned in traditional textbooks on Applied Statistics. The naive approach to equivalence testing, i.e. performing an ordinary two-sided test and inferring equivalence from the absence of a significant difference, is unacceptable since it entails an uncontrolled increase of the risk of false positive conclusions. A technically simple approach to avoiding such fallacies is based on the principle of confidence interval inclusion. However, the latter suffers from the disadvantage of yielding testing procedures that tend to exhibit comparatively poor power properties. For the sake of keeping the numbers of patients or subjects to be recruited for the respective trials as low as possible, application of optimum testing procedures, also for equivalence assessment, has much to recommend it. The rationale of such an optimum test for equivalence is described in some detail for four standard settings frequently encountered in clinical research.

Binomial Distribution↗
PubMed2000

Age-related reference ranges for fetal foot length.

AIM: The aim of this study was to establish age-dependent reference ranges for fetal foot length with gestation as well as for the femur/foot length ratio, based on a mathematical growth model. METHOD: In a prospective cross-sectional study of 610 pregnancies with sonographically confirmed gestational age (< 12 weeks' gestation), fetal biometry was performed in addition to measurements of fetal foot length between 12 and 42 completed weeks of gestation. Reference ranges for the fetal foot and for the femur/foot length ratio were constructed with an overall coverage of 90% of the measured data, using a previously established method of determining reference bands for growth parameters. RESULTS: Foot length was noted to level off slightly up to 24 weeks of gestation and it continued in a nearly linear fashion thereafter. The femur/foot length ratio was associated with a mean value of approximately 1 up to 24 weeks of gestation, falling to below 1 after this time point to a value of 0.85 at 41 weeks' gestation. The comparison of the reference ranges established in this study with anatomic and sonographic reference ranges for the fetal foot demonstrates good conformity with the anatomic reference range published by Streeter as early as 1920, and a large degree of conformity with the sonographic reference range developed by Mercer and co-workers. CONCLUSION: The proposed statistical approach offers reliable reference ranges for the fetal foot and for the femur/foot-ratio as well.

Cross-Sectional Studies↗
PubMed2000

Reference values of ductus venosus flow velocities and calculated waveform indices.

In recent years, investigations of the venous vascular system have become increasingly important in the assessment of fetal myocardial function. The aim of the present Doppler ultrasound study was to establish both new reference ranges for blood flow velocity during the different phases of the cardiac cycle (S, SD, D, a) and various calculated indices ((S-a)/S, (S-a)/V(mean), (S-a)D, S/D, a/S, S/a) for the ductus venosus. Pulsed-wave colour Doppler was used in this prospective cross-sectional study to examine 696 women with low-risk pregnancies during the period from 14 to 41 weeks' gestation. Reference curves were constructed for the individual measuring parameters based on a growth function from a four-parameter class of monotonic continuous functions according to the smallest square principle. A significant increase in blood flow velocity from 48 cm/s to 65.8 cm/s was observed during ventricular systole (=S) from 14 to 41 week's gestation. Similarly, increases in blood flow velocity were recorded during the endsystolic phase (=SD) (35.5 cm/s to 50.7 cm/s during early ventricular diastole (=D) (41.7 cm/s to 58 cm/s, p=0.0001) and atrial contraction (=a) (11.2 cm/s to 35 cm/s, p=0.0001), as well as for intensity-weighted mean velocity (30 cm/s to 48.3 cm/s). The venous indices were associated with significant decreases in the individual parameters with increasing gestational age: (S-a)/S from 0.77 to 0.47, (S-a)/V(mean) from 1.21 to 0.67, (S-a)/D from 0.89 to 0.54, S/a from 4.5 to 1.99. A significant increase from 0.23 to 0.53 was observed only for the quotient a/S. There were no changes in the S/D quotient (from 1.15 to 1.13). Regarding intra-observer reliability, more favourable results were obtained for calculated indices than for measurements of absolute blood flow velocities. At constant measuring conditions, the reference ranges established by this study for blood flow velocities and calculated indices in the ductus venosus may serve as the basis for Doppler ultrasound follow-up in a normal patient population as well as for the diagnosis of fetal myocardial insufficiency of hypoxic and congestive origin.

Adolescent↗
PubMed1997

Randomised, double blind, multicentre comparison of hydrochlorothiazide, atenolol, nitrendipine, and enalapril in antihypertensive treatment: results of the HANE study. HANE Trial Research Group.

OBJECTIVE: To compare the effectiveness and tolerability of hydrochlorothiazide, atenolol, nitrendipine, and enalapril in patients with mild to moderate hypertension. DESIGN: Randomised multicentre trial over 48 weeks with double blind comparison of treatments. SETTING: 48 centres in four countries. PATIENTS: 868 patients with essential hypertension (diastolic blood pressure 95-120 mm Hg) INTERVENTIONS: Initial treatment (step 1) consisted of 12.5 mg hydrochlorothiazide (n = 215), 25 mg atenolol (n = 215), 10 mg nitrendipine (n = 218), or 5 mg enalapril (n = 220) once daily. If diastolic blood pressure was not reduced to < 90 mm Hg within four weeks, doses were increased to 25 mg, 50 mg, 20 mg, 10 mg, respectively, once daily (step 2) and after two more weeks to twice daily (step 3). The eight week titration phase was followed by an additional 40 weeks for patients who had reached the target diastolic pressure. MAIN OUTCOME MEASURES: Blood pressure by means of an automatic device with repeated measurements. RESULTS: After eight weeks the response rate for atenolol (63.7%) was significantly higher than for enalapril (50.0%), hydrochlorothiazide (44.7%), or nitrendipine (44.5%). After one year atenolol was still more effective (48.0%) than hydrochlorothiazide (35.4%) and nitrendipine (32.9%), but not significantly better than enalapril (42.7%). The treatment related dropout rate was higher (P < 0.001) in the nitrendipine group (n = 28). CONCLUSIONS: There is no evidence of superiority for antihypertensive effectiveness or tolerability of the "new" classes of antihypertensives (calcium channel blockers and angiotensin converting enzyme inhibitors). As these drugs are now widely used as treatment of first choice, our results further emphasise the need for studies confirming that they also reduce morbidity and mortality, as has been shown for diuretics and beta blockers.

Adult↗
PubMed1997

[Transvaginal ultrasound biometry in early pregnancy--a growth model].

PURPOSE: Evaluation of a growth model for the biometric parameters of early pregnancy: Chorionic cavity, yolk sac, amniotic cavity, crown-rump length and biparietal diameter. METHOD: 618 clinically well-dated singleton pregnancies of the first trimester were measured in a prospective cross-sectional study with high-frequency transvaginal ultrasound between 28 and 94 days post menstruation. RESULTS: Normal curves (5th, 50th, 95th percentiles) for all parameters were established using our growth model. The growth curves of chorionic cavity amniotic cavity, and biparietal diameter showed a linear growth whereas the growth curve of the crown-rump-length represented an exponential curve. Linear growth of the yolk sac was found until 8 weeks of gestation and there was no growth alteration after this time. CONCLUSION: With our growth curves of the first trimester it is possible to monitor the embryonic development with several parameters.

Anthropometry↗
PubMed1997

A comment on so-called individual criteria of bioequivalence.

The idea of defining bioequivalence in terms of the proportion of individuals exhibiting a drug formulation discrepancy that does not exceed some prespecified limit seems natural enough. Since the derivation of formal statistical procedures for testing the associated hypotheses is more or less straightforward, it is surprising that the approach was pursued in a systematic manner not earlier then in 1990 [by Anderson and Hauck and Wellek]. In discussing the relative merits of the approach we will stress the importance of a careful understanding of its conceptual basis. It will be argued that the most severe limitation on the usefulness of such probability-based criteria of individual bioequivalence arises from the fact that large intraindividual formulation discrepancies provide evidence against equivalence only in definite absence of period effects.

Chemistry, Pharmaceutical↗
PubMed1996

Radical cystectomy with or without adjuvant polychemotherapy for non-organ-confined transitional cell carcinoma of the urinary bladder: prognostic impact of lymph node involvement.

OBJECTIVES: To analyze the effectiveness of adjuvant polychemotherapy after radical cystectomy for non-organ-confined transitional cell bladder cancer (Stages pT3b, pT4a, and/or pN1 or pN2). METHODS: Of 166 consecutive patients undergoing cystectomy at two institutions from 1987 to 1993, 80 received adjuvant polychemotherapy with methotrexate, vinblastine, and cisplatin plus doxorubicin (MVAC) or epirubicin (MVEC), whereas 86 had cystectomy only. The patients were evaluated for relapse-free survival and length of progression-free interval on the basis of follow-up data obtained in 1995 and 1996. RESULTS: Kaplan-Meier analysis revealed a significantly higher progression-free rate for patients after adjuvant chemotherapy (P = 0.0002, log-rank test). With and without adjuvant chemotherapy, prognosis declined in a stepwise manner, depending on the extent of lymph node involvement. Nevertheless, the superior prognosis of the chemotherapy group could be demonstrated at each lymph node stage. Of the 166 patients, 49 had initially entered a prospective trial comparing adjuvant with no adjuvant treatment. That study was discontinued in December 1990 after an interim analysis revealed a significant prognostic advantage in favor of the 26 patients randomized to receive chemotherapy compared with the 23 control patients. Current follow-up data continue to demonstrate a significant improvement in progression-free survival in favor of patients randomized to receive adjuvant chemotherapy (P = 0.0040). The follow-up period of patients living free of disease ranges from 58 to 96 months. CONCLUSIONS: Adjuvant chemotherapy with MVAC/MVEC leads to significant prolongation of relapse-free survival and improvement of the definitive cure rate after radical cystectomy for locally advanced transitional cell carcinoma of the urinary bladder.

Adult↗
PubMed1996

Sonographic size of uterus and ovaries in pre- and postmenopausal women.

Uterine and ovarian size were measured in 765 pre- and postmenopausal women by transvaginal ultrasound. Of these, 263 (premenopausal, n = 155; postmenopausal, n = 108) were found to have neither uterine nor ovarian pathological findings. According to parity, premenopausal women were separated into three groups: nullipara, primipara and multipara. Postmenopausal women were separated into two groups according to years since menopause: < or = 5 years and > 5 years since menopause. In the premenopausal group, a parity-related enlargement in uterine size was observed between nulliparous and parous women. After the menopause, a significant reduction in uterine size and in the corpus-cervix ratio was observed. The reduction in uterine size was related to years since menopause. The endometrial thickness measured in the group of premenopausal women did not exceed 4 mm on day 4 and 8 mm on day 8 of the menstrual cycle; in the postmenopausal group, endometrial thickness did not exceed 5 mm (mean 3.6 mm). In the group of premenopausal women, no parity-related change in ovarian volume was observed. After menopause, there was an obvious reduction in ovarian volume. Between the two postmenopausal groups, there was a small but significant difference in ovarian volume.

Adolescent↗
PubMed1996

[Normal fetal growth profile--a uniform model for calculating normal curves for current head and abdomen parameters and long limb bones].

AIM: Age-related and uniformly defined standard graphs were obtained for the fetal parameters BPD, OFD, HC, ATD, ASD, AC, Fe, Ti, Fi, Hu, Ra and Ul. METHODS: Data of 2032 healthy pregnant women of sonographically confirmed gestational age were used in a prospective cross-sectional study to establish reference charts for the fetal head and abdomen and the long limb bones. Only patients with an uncomplicated pregnancy were included in the study. The gestational age at which the measurements were taken ranged from 12 to 41 completed weeks. All measurements were performed as external-to-external measurements. RESULTS: By means of a mathematical model age related standard reference ranges were calculated on the basis of a single formula. Uniformly well-defined standard graphs were obtained for all parameters. All fetal parameters showed a nonlinear fetal growth. SUMMARY: Contrary to the common methods of creating reference standards by means of high-degree polynomials, the mathematical model presented here has the advantage of characterising the course of several parameters on the basis of one single formula. This is of great importance for digitising fetal charts in commercially available ultrasound machines.

Anthropometry↗