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PubMed1994

A microcomputer program for the design and analysis of phase II cancer clinical trials with two group sequential methods, the sequential probability ratio test, and the triangular test.

We developed an interactive and menu-driven computer program to help investigators design and analyze phase II cancer clinical trials with a group sequential method, namely the sequential probability ratio test or the triangular test. Based on the values selected for the parameters of the trial, the "Design" option allows one to obtain, using simulations, the statistical properties (type I and II error rates and the probability that the test accepts the hypothesis of inefficacy under 21 different assumptions) and the average sample size (under the same assumptions) of the selected test. The "Analysis" option (i) computes, at each analysis, the two statistics V and Z on which the sequential method is based and plots the sample path from the number of successes observed, and (ii), using asymptotic properties, gives the significance level of the test and a point estimate (with its 95% confidence interval) of the parameter of interest at the last analysis.

Algorithms↗
PubMedDate not supplied

Cryo-electron-microscopy reconstruction of partially symmetric objects.

A procedure is described for reconstructing three-dimensional objects from two-dimensional projections. The method is based both on the original Crowther, DeRosier, and Klug (DeRosier, D.J., and Klug, A. (1968), Nature 217, 130-134; Crowther, R.A., DeRosier, D.J., and Klug, A. (1970) Proc. R. Soc. London A 317, 319-340) work on image reconstructions of icosahedral viruses and on the concept of noncrystallographic symmetry (Rossmann, M.G., 1995, Curr. Opin. Struct. Biol. 5, 650-655). The procedure has been applied so far only to test data where the objective has been the determination of particle orientation, both ab initio and through the use of model data.

Cryoelectron Microscopy↗
PubMed1997

Combining spatial extent and peak intensity to test for activations in functional imaging.

Within the framework of statistical mapping, there are up to now only two tests used to assess the regional significance in functional images. One is based on the magnitude of the foci and tends to detect high intensity signals, while the second is based on the spatial extent of regions defined by a simple thresholding of the statistical map, a test that is more sensitive to extended signals. The aim of this paper is to combine the two tests into a single test that is more sensitive to a wider range of signals. This combined test is based on an analytical approximation of the distribution of these two parameters (size and height) and is applied in the context of statistical maps. The risk of error in noise-only 2D or 3D volumes is assessed under a wide range of experimental conditions obtained by varying both the resolution of the map and the threshold at which clusters are defined. In addition, we have investigated this new test on simulated signals, and applied it to an experimental PET dataset. The experimental risk of error is close to the predicted one, and the overall sensitivity increases when analyzing a volume containing different types of signals.

Adult↗
PubMed2001

Modeling geometric deformations in EPI time series.

Even after realignment there is residual movement-related variance present in fMRI time-series, causing loss of sensitivity and, potentially, also specificity. One cause is the differential deformation of the sampling matrix, by field inhomogeneities, at different object positions, i.e., a movement-by-inhomogeneity interaction. This has been addressed previously by using empirical field measurements. In the present paper we suggest a forward model of how data is affected by an inhomogeneous field at different object positions. From this model we derive a method to solve the inverse problem of estimating the field inhomogeneities and their derivatives with respect to object position, directly from the EPI data and estimated realignment parameters. The field is modeled as a linear combination of cosine basis fields, which facilitates a fast way of implementing the necessary matrix operations. Simulations suggest that the solution is tractable and that the fields are estimable given the deformed images and knowledge of the relative positions at which they have been acquired. An experiment on a subject performing voluntary movements in the scanner yielded plausible estimates of the deformation fields and their application to "unwarp" the time series significantly reduced movement-related variance.

Adult↗
PubMed2001

Deformation-based morphometry and its relation to conventional volumetry of brain lateral ventricles in MRI.

Deformation-based morphometry (DBM) is a useful technique to detect morphological differences over the entire brain since it analyses positional differences between every voxel and a standard brain. In this report we compare DBM to semimanual tracing of brain ventricles in a population of 39 patients with schizophrenia. High-resolution T(1)-weighted magnetic resonance images were obtained and processed with DBM and interactive tracing software. We evaluate the validity of the DBM in two different approaches. First, we divide subjects into two groups based on the mean ventricular/brain ratios and compute statistical maps of displacement vectors and their spatial derivatives. This analysis demonstrates a striking consistency of the DBM and visual tracing results. We show that restricting the information about the deformation fields by computing the local Jacobian determinant (as a measure of volume change) provides evidence of the shape of ventricular deformation which is unavailable from ventricular volume measures alone. Second, we compute a mean measure of the Jacobian values over the entire ventricles and observe a correlation of r = 0.962 with visual tracing based ventricular/brain ratios. The results support the usefulness and validity of DBM for the local and global examination of brain morphology.

Adolescent↗
PubMed2002

Thresholding of statistical maps in functional neuroimaging using the false discovery rate.

Finding objective and effective thresholds for voxelwise statistics derived from neuroimaging data has been a long-standing problem. With at least one test performed for every voxel in an image, some correction of the thresholds is needed to control the error rates, but standard procedures for multiple hypothesis testing (e.g., Bonferroni) tend to not be sensitive enough to be useful in this context. This paper introduces to the neuroscience literature statistical procedures for controlling the false discovery rate (FDR). Recent theoretical work in statistics suggests that FDR-controlling procedures will be effective for the analysis of neuroimaging data. These procedures operate simultaneously on all voxelwise test statistics to determine which tests should be considered statistically significant. The innovation of the procedures is that they control the expected proportion of the rejected hypotheses that are falsely rejected. We demonstrate this approach using both simulations and functional magnetic resonance imaging data from two simple experiments.

Adult↗
PubMed2002

Sexual dimorphism in the corpus callosum: a characterization of local size variations and a classification driven approach to morphometry.

We present two complementary quantitative approaches to the problem of characterizing morphometric variations between two distinct populations. The case presented focuses solely on local size variations, but the general method can easily be applied to other scalar morphometric quantities. The first method uses a statistical parametric map (SPM) to ascertain a P value, which indicates whether any statistically significant differences exist between the populations. The second method focuses on finding the best single measurement which can be used for classifying the two populations. For our case study midsagittal cross sections of the corpora callosa from a population of normal males and females are nonrigidly registered (spatially normalized) to an atlas. The resulting deformations are then used to ascertain (i) whether there are any statistically significant differences between the populations and (ii) whether these differences allow one to perform classification. We make use of the Jacobian of the deformation field and normalize it to account for overall volume changes allowing us to focus on differences which are more related to morphometry than scale. From the (SPM) approach to the problem we find evidence of statistically significant differences in the morphology between the populations. Using a linear discriminant function we find that these differences do not appear to be useful for classification. Thus, this dataset provides an example of how statistically significant effects may not be of much diagnostic value. They may be of interest to the research community, but of little value to the clinician.

Adult↗
PubMed1996

Brownian dynamics simulation of the lateral distribution of charged membrane components.

Brownian dynamics simulations were performed to study the contribution of electric interactions between charged membrane components to their lateral distribution in a two-dimensional viscous liquid (bilayer lipid membrane). The electrostatic interaction potential was derived from an analytical solution of the linearized Poisson-Boltzmann equation for point charges in an electrolyte solution--membrane--electrolyte solution system. Equilibrium as well as dynamic quantities were investigated. The lateral organization of membrane particles, modelled by mobile cylinders in a homogeneous membrane separating two electrolyte solutions was described by spatial distribution functions, diffusion coefficients and cluster statistics. Disorder, local order and crystal-like arrangements were observed as a function of the particle charge, the closest possible distances between the charges and the particle density. The simulations revealed that the system is very sensitive to the position of the charges with respect to the electrolyte solution-membrane interface. Electrostatic interactions of charges placed directly on the membrane surface were almost negligible, whereas deeper charges demonstrated pronounced interaction. Biologically relevant parameters corresponded at most to local and transient ordering. It was found that lateral electric forces can give rise to a preferred formation of clusters with an even number of constituents provided that the closest possible charge-charge distances are small. It is concluded that lateral electrostatic interactions can account for local particle aggregations, but their impact on the global arrangement and movement of membrane components is limited.

Cell Membrane↗
PubMed1992

Building population pharmacokinetic--pharmacodynamic models. I. Models for covariate effects.

One major task in clinical pharmacology is to determine the pharmacokinetic-pharmacodynamic (PK-PD) parameters of a drug in a patient population. NONMEM is a program commonly used to build population PK-PD models, that is, models that characterize the relationship between a patient's PK-PD parameters and other patient specific covariates such as the patient's (patho) physiological condition, concomitant drug therapy, etc. This paper extends a previously described approach to efficiently find the relationships between the PK-PD parameters and covariates. In a first step, individual estimates of the PK-PD parameters are obtained as empirical Bayes estimates, based on a prior NONMEN fit using no covariates. In a second step, the individual PK-PD parameter estimates are regressed on the covariates using a generalized additive model. In a third and final step, NONMEM is used to optimize and finalize the population model. Four real-data examples are used to demonstrate the effectiveness of the approach. The examples show that the generalized additive model for the individual parameter estimates is a good initial guess for the NONMEM population model. In all four examples, the approach successfully selects the most important covariates and their functional representation. The great advantage of this approach is speed. The time required to derive a population model is markedly reduced because the number of necessary NONMEM runs is reduced. Furthermore, the approach provides a nice graphical representation of the relationships between the PK-PD parameters and covariates.

Adult↗
PubMed1998

A new approach for on-resonance magnetization transfer parameter optimization.

On-resonance radio frequency pulse sequences for magnetization transfer are optimized using a frequency domain approach. The method presented here was developed using binomial pulses and it is demonstrated that a simple analysis leads to accurate sequence parameters that can be used directly for magnetic resonance imaging. With thus optimized parameters it is possible to produce an efficient saturation of protons having short transverse relaxation time while protons with long transverse relaxation time are kept nearly unaffected by the radio frequency. The method is particularly well suited to the design of new magnetization transfer sequences and to the estimation of the limits of the accuracy of a T2 selection. Additionally in vitro tests have been performed on beef tendon oriented with a zero fiber to field angle.

Computer Simulation↗
PubMed2003

[Navigated osteosynthesis of the proximal femur. An experimental study].

Screw position in femoral head has been considered the most important predictive factor for mechanical failure in pertrochanteric osteosynthesis, and correct positioning is assisted by fluoroscopic control. Although fluoroscopy leads to precise and reproducible results, it is associated with scattered radiation to the patient and surgical staff. Computer-assisted surgery (CAS) may be an alternative in means of achieving precise screw insertion with a low radiation dose. We designed a laboratory study in which artificial proximal femora were submitted to insertions of a dynamic hip screw (DHS) and an anti-rotational screw (ARS). Three set-ups were tested: (1) conventional implantation with two simultaneous C-arms using a guide wire; (2) drilling and implantation controlled by CAS solely with a 3.2-mm drill bit, then insertion of a guide wire and drilling for the dynamic hip screw; (3) after navigated drilling (3.2 mm) a fluoroscopic control was performed. Five variables were used comparing methods and surgeons: operation time, radiation time, tip-apex distance (TAD), and the insertion neck-shaft angles of DHS and ARS. Considering TAD as a precision parameter, CAS led to screw insertion as accurate as with fluoroscopic control, with a reduction of radiation time up to 93%.

Analysis of Variance↗
PubMed2004

[Change of offset after implantation of hip alloarthroplasties].

The purpose of the present study was to evaluate the change of the offset after implantation of hip alloarthroplasties. In an experimental study the X-ray templates of 90 different implants (594 different sizes) were digitized (cup and stem) and virtually implanted in the hip joint of 50 consecutive patients who were on the waiting list for hip replacement. Implantation was performed on AP X-rays paying heed to the fit of the shaft and adequate leg length. In total 4500 implantations were performed. After virtual implantation the change of the offset was calculated. There was a wide variance in the ability to fit the implants to the individual patient. For some patients it seems to be extremely difficult to adapt the implant without changing the offset. Some implant designs were only suitable for 2 patients while other designs were suitable for 40 patients (mean: 17). The average change of the offset was 0.27 cm. Considering only the cases in which a change occurs this value increases up to 0.56 cm.For the individual patient the average number of implants that were suitable was 30 (range: 1-67) of a total of 90 designs. Here the average change of the offset was 0.4 cm (-1.04 -- +1.54 cm). Considering only the cases in which a change occurs this value increases up to 0.64 cm. In the majority of the cases the presently available implants do not allow anatomic reconstruction of the individual offset.

Bone Malalignment↗
PubMed1998

[Volumetric brain findings in late depression. A study with quantified magnetic resonance tomography].

A number of observations including clinical manifestation, course, outcome, and family history, support the view that patients presenting with a major depression occurring first in late life should be treated as a nosological subgroup. In this study quantitative magnetic resonance imaging (MRI) was used to investigate volumes of different brain structures in 19 patients with late onset major depression (age of onset > 50) and 13 age matched controls. 3-D MRI sequences were acquired using a Siemens 1.5T scanner. Whole brain volume, CSF volume, volume of the frontal and temporal lobes and the volume of the amygdala-hippocampus complex were assessed using the software NMRWin. Compared to the controls, depressed patients showed a significantly lower whole brain volume and a significantly higher CSF volume, whereas volumes of the frontal and temporal lobes as well as the amygdala-hippocampus complex volumes were not significantly decreased. In addition, depressed patients exhibited a higher ventricle-brain ratio suggesting a higher degree of central atrophy compared to healthy individuals. Our results indicate that cerebral changes involving subcortical structures are of relevance in the pathogenesis of late-onset depression. Defining the aetiology of these lesions may be important for the development of preventive treatment of depression in the elderly.

Aged↗
PubMed2003

Can pre-operative contrast-enhanced dynamic MR imaging for prostate cancer predict microvessel density in prostatectomy specimens?

The aim of this study was to correlate quantitative dynamic contrast-enhanced MRI (DCE MRI) parameters with microvessel density (MVD) in prostate carcinoma. Twenty-eight patients with biopsy-proven prostate carcinoma were examined by endorectal MRI including multiplanar T2- and T1-weighted spin-echo and dynamic T1-weighted turbo-FLASH MRI during and after intravenous Gd-DTPA administration. Microvessels were stained on surgical specimens using a CD31 monoclonal antibody. The MVD was quantified in hot spots by counting (MVC) and determining the area fraction by morphometry (MVAF). The DCE MRI data were analyzed using an open pharmacokinetic two-compartment model. In corresponding anatomic locations the time shift (Deltat) between the beginning of signal enhancement of cancer and adjacent normal prostatic tissue, the degree of contrast enhancement and the contrast exchange rate constant (k21) were calculated. The MVC and MVAF were elevated in carcinoma (p<0.001 and p=0.002, respectively) and correlated to k21 (r=0.62, p<0.001 and r=0.80, p<0.001, respectively). k21-values of carcinoma were significantly higher compared with normal peripheral but not central zone tissue. Deltat was longer in high compared with low-grade tumors (p=0.025). The DCE MRI can provide important information about individual MVD in prostate cancer, which may be helpful for guiding biopsy and assessing individual prognosis.

Aged↗
PubMed2005

Evaluation of an improved technique for automated center lumen line definition in cardiovascular image data.

The aim of the study was to evaluate a new method for automated definition of a center lumen line in vessels in cardiovascular image data. This method, called VAMPIRE, is based on improved detection of vessel-like structures. A multiobserver evaluation study was conducted involving 40 tracings in clinical CTA data of carotid arteries to compare VAMPIRE with an established technique. This comparison showed that VAMPIRE yields considerably more successful tracings and improved handling of stenosis, calcifications, multiple vessels, and nearby bone structures. We conclude that VAMPIRE is highly suitable for automated definition of center lumen lines in vessels in cardiovascular image data.

Algorithms↗
PubMed2005

Variants of the superior labrum and labro-bicipital complex: a comparative study of shoulder specimens using MR arthrography, multi-slice CT arthrography and anatomical dissection.

The purpose of the present study was to evaluate the anatomical variability of the superior labrum and to compare the value of MR arthrography and multi-slice CT arthrography in the diagnosis of variants of the labro-bicipital complex. Forty-three human shoulder specimens (age range and mean age at death, 61-89 years and 78.3 years) were examined with the use of MR arthrography and multi-slice CT arthrography prior to joint exploration and macroscopic inspection of the superior labrum and labro-bicipital complex. Two radiologists evaluated MR and CT arthrograms, and the results were compared with macroscopic assessments. Anatomical dissection of all shoulder specimens revealed a sublabral recess in 32/43 (74%) cases. The attachment of the superior labrum was categorised as type 1 in ten (23%) cases, as type 2 in eight (19%), as type 3 in ten (23%), and as type 4 in 14 (33%) cases. One superior labrum showed detachment consistent with a superior labral anteroposterior (SLAP) type 3 lesion. On MR arthrography and CT arthrography the attachment of the superior labrum was categorised in concordance with macroscopic assessments in 79% and 84% of cases, respectively. The anteroposterior extension of sublabral recesses was accurately determined with MR and CT arthrography in 59% and 81% of cases, respectively. The attachment of the superior labrum shows considerable variability. Thus, exact depiction of variants is essential in order to avoid the false positive diagnosis of a superior labral tear (SLAP or Andrews lesion). Both, MR arthrography and multi-slice CT arthrography were effective in the detection and classification of sublabral recesses.

Aged↗
PubMed2007

Value of MR phase-contrast flow measurements for functional assessment of pulmonary arterial hypertension.

Goals of our study were to compare the pulmonary hemodynamics between healthy volunteers and patients with pulmonary arterial hypertension (PAH) and correlate MR flow measurements with echocardiography. Twenty-five patients with PAH and 25 volunteers were examined at 1.5 T. Phase-contrast flow measurements were performed in the ascending aorta and pulmonary trunk, resulting in the following parameters: peak velocity (cm/s), average blood flow (l/min), time to peak velocity (ms), velocity rise gradient and pulmonary distensibility (cm(2)). The bronchosystemic shunt was calculated. In PAH patients transthoracic echocardiography and right-heart catheterization (RHC) served as the gold standard. In comparison to volunteers, the PAH patients showed significantly reduced pulmonary velocities (P = 0.002), blood flow (P = 0.002) and pulmonary distensibility (P = 0.008). In patients, the time to peak velocity was shorter (P<0.001), and the velocity rise gradient was steeper (P = 0.002) than in volunteers. While in volunteers the peak velocity in the aorta was reached earlier, it was the reverse in patients. Patients showed a significant bronchosystemic shunt (P = 0.01). No meaningful correlation was found between MRI measurements and echocardiography or RHC. MRI is a feasible technique for the differentiation between PAH and volunteers. Further studies have to be conducted for the absolute calculation of pressure estimates.

Adult↗
PubMed2003

[Left ventricular mass in endurance-athletes with athlete's heart and untrained subjects--comparison between different echocardiographic methods and MRI].

UNLABELLED: The echocardiographic determination of left ventricular mass (LVM) and volume is of importance for the interpretation of cardiac adaptations and risk-stratification. In pathologically hypertrophied hearts, conventional one- and two-dimensional echocardiographic methods tend to overestimate LVM. For the athlete's heart, a comparison between different echocardiographic methods and magnetic resonance imaging (MRI) has not been performed so far. 23 healthy male endurance-athletes (28+/-4 yr) with athlete's heart (A) and 26 healthy untrained males (U; 26+/-4 yr) were examined by MRI and the following echocardiographic methods: ASE-Cube (ASE), Devereux (DEV), Troy (TRO), Teichholz (TEI), Reichek (REI) and Dickhuth (DIC). Indexed LVM were: MRI: 107+/-6 g/m(2) (A), 79+/-7 g/m(2) (U); ASE: 170+/-20 g/m(2) (A), 119+/-14 g/m(2) (U); DEV: 134+/-16 g/m(2) (A), 95+/-11 g/m(2) (U); TRO: 134+/-16 g/m(2) (A), 92+/-12 g/m(2) (U); TEI: 115+/-10 g/m(2) (A), 91+/-8 g/m(2) (U); REI: 114+/-14 g/m(2) (A), 89+/-11 g/m(2) (U); DIC: 110+/-14 g/m(2) (A); 80+/-9 g/m(2) (U). In A and U, LVM is significantly overestimated by ASE, DEV, TRO, TEI, and REI compared to MRI (p<0.05), but not by DIC. Although coefficients of correlation were similar, only DIC revealed acceptable limits of agreement (ASE: +20 to +172 g; DEV: -13 to +93 g; TRO: -18 to +92 g; TEI: -17 to +53 g; REI: -25 to +57 g; DIC: -37 to +45 g). Depending on the used method, LVM upper limits range between 93 (MRT) and 146 g/m(2) (ASE) in U, and 119 (MRT) and 209 g/m(2) (ASE) in A. CONCLUSION: Compared to MRI, DIC is the most accurate conventional echocardiographic method to determine LVM in U and A. For a correct interpretation of LVM, differences of the echocardiographic methods have to be considered.

Adult↗