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PubMed1995

Graphical models for panel studies, illustrated on data from the Framingham Heart Study.

Recursive graphical models allow description of the simultaneous development of several (discrete) characteristics such as are recorded in a panel study. Irreversible events (death, irreversible disease occurrence) between exams are naturally included. This paper reviews these models and gives a detailed discussion of an example consisting of 49-50 year old males from the Framingham Heart study. The program DIGRAM is used throughout and the present paper may also serve as an introduction to this software.

Cause of Death↗
PubMed1993

Monte Carlo analysis of the conformation of DNA catenanes.

We used a Monte Carlo method to study the conformational properties of catenanes between two nicked DNA rings. We calculated the writhe induced by catenation as a function of the linking number between the two rings. The simulations modeled catenated rings of equal size as well as rings differing in length by a factor of 3. For both classes of catenanes, the calculated values of writhe agreed very well with the experimental measurements of catenation-induced supercoiling made by Wasserman et al. Therefore, the equilibrium value of DNA twist is not changed significantly by catenation. We found that the induced writhe increased linearly with catenane linking number, but was independent of DNA length and of effective helical diameter. We conclude that induced writhe is a general feature of catenation, and that it depends primarily on the ratio of lengths of the linked rings and the number of catenane interlocks. In contrast, catenane conformation varied qualitatively with catenation linking number, DNA length, and double helix diameter. At the values of these parameters for catenanes isolated from cells, catenane conformations were strikingly irregular. Nonetheless, the local concentration of two sites on separate but linked rings increased greatly with catenane linking number. This increase is similar to that brought about by (-) supercoiling to DNA sites in cis.

Computer Simulation↗
PubMed2001

A global estimator unbiased by local changes.

The global activity is an important confound when analyzing PET data in that its inclusion in the statistical model can substantially reduce error variance and increase sensitivity. However, by defining global activity as the average over all voxels one introduces a bias that is collinear with experimental factors. This leads to an underestimation of true activations and the introduction of artefactual deactivations. We propose a novel estimator for the global activity based on the notion of finding a maximally nonlocal mode in a multivariate characterization of the data, while maximizing the locality of the remaining modes. The approach uses singular value decomposition (SVD) to find a provisional set of modes, which are subsequently rotated such that a metric based on the above heuristic is maximized. This metric is a version of the stochastic sign change (SSC) criterion that has been used previously for normalizing medical images with focal defects. The estimator was evaluated on simulated and real functional imaging (PET) data. The simulations show that the bias of the global mean, introduced by focal activations, is reduced by 80--90% with the new estimator. Comparison with a previous unbiased estimator, using the empirical data, yielded similar results. The advantage of the new estimator is that it is not informed of experimental design and relies only on general assumptions regarding the nature of the signal.

Brain↗
PubMed1992

Algorithms to rapidly achieve and maintain stable drug concentrations at the site of drug effect with a computer-controlled infusion pump.

Computer-controlled infusion pumps incorporating an internal model of drug pharmacokinetics can rapidly achieve and maintain constant drug concentrations in the plasma. Although these pumps offer more accurate titration of intravenous drugs than is possible with simple boluses or constant rate infusions, the choice of the plasma as the target site is arbitrary. The plasma is not the site of drug effect for most drugs. This manuscript describes two algorithms for calculation of the infusion rates necessary for a computer-controlled infusion pump to rapidly achieve, and then maintain, the desired target concentration at the site of drug effect rather than in the plasma.

Animals↗
PubMed2004

[The accuracy of palpation from orientation points for the navigated implantation of knee prostheses].

AIMS: Cinematic and pointing procedures are used for non-image based navigated implantation during total knee replacement. Pointing procedures require an exact knowledge of the landmarks. In this anatomical study, landmarks are defined and repeatedly referenced. Precision and reproducibility are evaluated by means of an inter- and an intra-observer study. The axes of the femur and tibia are calculated using the landmarks. MATERIAL AND METHODS: The specific landmarks of 30 femurs and 27 tibias were palpated by three surgeons and digitised by means of a photogrammetric system, as used intra-operatively. The recorded data were statistically evaluated. RESULTS: The specific landmarks can be referenced with great precision. The vectors that influence the implant position show a mean femoral deviation of 0.9 mm and a mean tibial deviation of 1.0 mm. The repeating accuracy of every observer was 1.5 mm femoral and 1.0 mm tibial. The calculated long axes at the femur and tibia thus reach a precision of 0.1 degrees (min.-max.: 0-0.9 degrees) at the femur and 0.2 degrees (.0-1.1 degrees) at the tibia. The short axes at the distal femur and proximal tibia exhibit an average deviation of from 0.7 degrees to 1.9 degrees (0-11.3 degrees). CONCLUSION: Long axes (mechanical axes) can be determined exactly but the precision of the short axes (rotational axes) is unsatisfactory, although palpation of landmarks was accurate. Therefore, palpation of more than one rotational axis at the femur and tibia is mandatory and should be visualized on the monitor during surgery.

Arthroplasty, Replacement, Knee↗
PubMed2004

[Possibilities of computer-assisted navitation in knee para-articular osteotomies].

Osteotomies in the knee region for incipient osteoarthritis in active patients have become increasingly popular in recent years. A computer-guided navigation system should help increase the surgeon's accuracy and lower the risk of intraoperative complications for this technically demanding type of surgery. Furthermore, computer navigation might be a powerful research and educational tool. The technical principles and the clinical implications of this system for knee osteotomies are described in the following article.

Bone Malalignment↗
PubMed2004

Normal coordinate analyses of 3,5-dichlorophenylcyanamide.

The structure of 3,5-dichlorophenylcyanamide c-C6H3Cl2-NHCN was investigated by DFT-B3LYP and ab initio MP2 calculations with the 6-311+G** basis set. The planar to perpendicular rotational barrier was calculated to be of about 5 kcal mol(-1) at both levels of calculation. The stability of the planar structure of the molecule was explained on the basis of conjugation effects between the cyanamide-NHCN moiety and the phenyl c-C6H5 ring in agreement with earlier NMR results. The CNC and the HNC bond angles were calculated to be about 120 degrees especially by MP2 calculation, which is consistent with sp2 (planar -NH-CN group) and not sp3 (pyramidal -NH-CN group) structure. The vibrational frequencies of the d0, d1 and d3 species of 3,5-dichlorophenylcyanamide and the potential energy distributions among symmetry coordinates of the normal modes of the parent molecule were computed at the DFT-B3LYP level. The calculated infrared and Raman spectra of the molecule were plotted. Complete vibrational assignments were made on the basis of isotopic substitution and normal coordinate calculations.

Biophysics↗
PubMed1986

A validation study of a simulation model for common source epidemics.

We consider an environment and a population of individuals who are susceptible to a disease caused by a pathogen spread from a common source. We view the sequence of events resulting in the illness of some individuals as consisting of three components: the introduction of the pathogens and their dispersion through the environment, the movement of susceptible individuals through the environment, and the physiological effects of exposure of susceptible individuals to various pathogen levels. We identify four important parameters: two for each of the first and third components. A computer simulation of a model with these features is developed and implemented to study a 1977 outbreak of toxoplasmosis. Questions of parameter estimation and model validation are considered in detail.

Computer Simulation↗
PubMed1990

Femoral head apparent density distribution predicted from bone stresses.

A new theory relating bone morphology to applied stress is used to predict the apparent density distribution in the femoral head and neck. Cancellous bone is modeled as a self-optimizing material and cortical bone as a saturated (maximum possible bone density) response to stress in the bone tissue. Three different approaches are implemented relating bone apparent density to: (1) the von Mises stress, (2) the strain energy density in the mineralized tissue and (3) a defined closed effective stress (spherical stress). An iterative nonlinear three-dimensional finite element model is used to predict the apparent density distribution in the femoral head and neck for each of the three approaches. It is shown that the von Mises stress (an open effective stress) cannot accurately predict bone apparent density. It is shown that strain energy density and the defined closed effective stress can predict apparent density and that they give predictions consistent with the observed density pattern in the femoral head and neck.

Bone Density↗
PubMed1990

Study of stress concentration in the walls of the bovine coronary arterial branch.

The intramural stress concentration in the arterial wall is studied at the bovine circumflex coronary arterial branch. The material properties, geometry, and strains in the arterial branch are determined from experiments. The stresses are determined using a finite element analysis. The arterial branch is modeled as two interesecting thin cylindrical shells incorporating local variations in the branch geometry, thickness, and material properties. The artery is considered orthotropic and loaded with an incremental pressure of 40 mmHg. The highest intramural stresses are found to be localized at the proximal and distal regions of the ostium and are not significantly affected by the elastic properties. The stresses are 3 to 4 times greater in the branch at the inner surface than in the straight segment. The strains are twice as large at the branch than in the straight segment. We speculate that this stress concentration could injure the artery and make the branch region susceptible to atherosclerosis.

Animals↗
PubMed1994

Analyzing the performance of diagnostic tests.

When a single diagnostic test is used to assess the disease state of a patient, the classic univariate measures of sensitivity and specificity are used. When combining two or more diagnostic tests, other methods provide alternative methods for assessing the utility of combining these tests. We have written and tested a program in FORTRAN that computes the univariate statistics and bivariate concordant/discordant statistics analyses of all possible combinations of diagnostic tests as compared with the 'gold standard'.

Confidence Intervals↗
PubMed2005

Handling outliers in brain tumour MRS data analysis through robust topographic mapping.

Uncertainty is inherent in medical decision making and poses a challenge for intelligent technologies. This paper focuses on magnetic resonance spectra (MRS) for discrimination of brain tumour types and grades. Modelling of this type of high-dimensional data is commonly affected by uncertainty caused by the presence of outliers. Multivariate data clustering and visualization of MRS data is proposed using the GTM framework with basis functions comprising Student t-distributions in order to minimize the negative impact on the model from outliers. The effectiveness of this model on the MRS data is demonstrated empirically.

Brain↗
PubMed2004

Electrical neuroimaging based on biophysical constraints.

This paper proposes and implements biophysical constraints to select a unique solution to the bioelectromagnetic inverse problem. It first shows that the brain's electric fields and potentials are predominantly due to ohmic currents. This serves to reformulate the inverse problem in terms of a restricted source model permitting noninvasive estimations of Local Field Potentials (LFPs) in depth from scalp-recorded data. Uniqueness in the solution is achieved by a physically derived regularization strategy that imposes a spatial structure on the solution based upon the physical laws that describe electromagnetic fields in biological media. The regularization strategy and the source model emulate the properties of brain activity's actual generators. This added information is independent of both the recorded data and head model and suffices for obtaining a unique solution compatible with and aimed at analyzing experimental data. The inverse solution's features are evaluated with event-related potentials (ERPs) from a healthy subject performing a visuo-motor task. Two aspects are addressed: the concordance between available neurophysiological evidence and inverse solution results, and the functional localization provided by fMRI data from the same subject under identical experimental conditions. The localization results are spatially and temporally concordant with experimental evidence, and the areas detected as functionally activated in both imaging modalities are similar, providing indices of localization accuracy. We conclude that biophysically driven inverse solutions offer a novel and reliable possibility for studying brain function with the temporal resolution required to advance our understanding of the brain's functional networks.

Biophysics↗
PubMed2004

Measuring interregional functional connectivity using coherence and partial coherence analyses of fMRI data.

Understanding functional connectivity within the brain is crucial to understanding neural function; even the simplest cognitive operations are supported by highly distributed neural circuits. We developed a novel method to measure task-related functional interactions between neural regions by applying coherence and partial coherence analyses to functional magnetic resonance imaging (fMRI) data. Coherence and partial coherence are spectral measures that estimate the linear time-invariant (LTI) relationship between time series. They can be used to generate maps of task-specific connectivity associated with seed regions of interest (ROIs). These maps may then be compared across tasks, revealing nodes with task-related changes of connectivity to the seed ROI. To validate the method, we applied it to an event-related fMRI data set acquired while subjects performed two sequence tapping tasks, one of which required more bimanual coordination. Areas showing increased functional connectivity with both tasks were the same as those showing increased activity. Furthermore, though there were no significant differences in mean activity between the two tasks, significant increases in interhemispheric coherence were found between the primary motor (M1) and premotor (PM) regions for the task requiring more bimanual coordination. This increase in interhemispheric connectivity is supported by other brain imaging techniques as well as patient studies.

Adolescent↗
PubMed2004

Variation of BOLD hemodynamic responses across subjects and brain regions and their effects on statistical analyses.

Estimates of hemodynamic response functions (HRF) are often integral parts of event-related fMRI analyses. Although HRFs vary across individuals and brain regions, few studies have investigated how variations affect the results of statistical analyses using the general linear model (GLM). In this study, we empirically estimated HRFs from primary motor and visual cortices and frontal and supplementary eye fields (SEF) in 20 subjects. We observed more variability across subjects than regions and correlated variation of time-to-peak values across several pairs of regions. Simulations examined the effects of observed variability on statistical results and ways different experimental designs and statistical models can limit these effects. Widely spaced and rapid event-related experimental designs with two sampling rates were tested. Statistical models compared an empirically derived HRF to a canonical HRF and included the first derivative of the HRF in the GLM. Small differences between the estimated and true HRFs did not cause false negatives, but larger differences within an observed range of variation, such as a 2.5-s time-to-onset misestimate, led to false negatives. Although small errors minimally affected detection of activity, time-to-onset misestimates as small as 1 s influenced model parameter estimation and therefore random effects analyses across subjects. Experiment and analysis design methods such as decreasing the sampling rate or including the HRF's temporal derivative in the GLM improved results, but did not eliminate errors caused by HRF misestimates. These results highlight the benefits of determining the best possible HRF estimate and potential negative consequences of assuming HRF consistency across subjects or brain regions.

Adolescent↗
PubMed2004

Less white matter concentration in autism: 2D voxel-based morphometry.

Autism is a neurodevelopmental disorder affecting behavioral and social cognition, but there is little understanding about the link between the functional deficit and its underlying neuroanatomy. We applied a 2D version of voxel-based morphometry (VBM) in differentiating the white matter concentration of the corpus callosum for the group of 16 high functioning autistic and 12 normal subjects. Using the white matter density as an index for neural connectivity, autism is shown to exhibit less white matter concentration in the region of the genu, rostrum, and splenium removing the effect of age based on the general linear model (GLM) framework. Further, it is shown that the less white matter concentration in the corpus callosum in autism is due to hypoplasia rather than atrophy.

Adolescent↗