Prospective evaluation of a Holter-ECG derived severity index for screening of sleep disordered breathing.

BACKGROUND AND PURPOSE: To prospectively evaluate the applicability of a method to screen overnight Holter-ECGs for sleep disordered breathing (SDB) in an unselected clinical routine Holter sample. METHODS: Holter-ECG recordings in 50 cardiologic inpatients were complemented with nocturnal respiratory polygraphy (PG). The respiratory event index (REI) and apnea/hypopnea index (AHI) from the PG served as a reference for an ECG-derived SDB severity estimate using a previously developed method. Agreement with the PG was investigated using Bland-Altman plots color-coded by ectopy level, and screening accuracy for REI≥15/h and AHI≥15/h was assessed. RESULTS: Prevalence for REI≥15/h was 52%, and 32% for AHI≥15/h. We observed better agreement of the ECG-based estimate with the REI compared to the AHI. Ectopy did not limit the detection of SDB. Binary screening for REI≥15/h provided excellent specificity of 0.96 with a sensitivity of 0.77. Ternary screening for AHI≥15/h yielded 16% borderline classifications and specificity/sensitivity of 0.96/0.86 for the remaining data. CONCLUSIONS: Screening of routine Holter-ECGs for sleep disordered breathing is reasonable and promises earlier identification of a significant part of patients at no additional cost.

Radial, spiral and reverberating waves of spreading depolarization occur in the gyrencephalic brain.

OBJECTIVES: The detection of the hemodynamic and propagation patterns of spreading depolarizations (SDs) in the gyrencephalic brain using intrinsic optical signal imaging (IOS). METHODS: The convexity of the brain surface was surgically exposed in fourteen male swine. Within the boundaries of this window, brains were immersed and preconditioned with an elevated K(+) concentration (7 mmol/l) in the standard Ringer lactate solution for 30-40 min. SDs were triggered using 3-5 µl of 1 mol/l KCl solution. Changes in tissue absorbency or reflection were registered with a CCD camera at a wavelength of 564 nm (14 nm FWHM), which was mounted 25 cm above the exposed cortex. Additional monitoring by electrocorticography and laser-Doppler was used in a subset of animals (n=7) to validate the detection of SD. RESULTS: Of 198 SDs quantified in all of the experiments, 187 SDs appeared as radial waves that developed semi-planar fronts. The morphology was affected by the surface of the gyri, the sulci and the pial vessels. Other SD patterns such as spirals and reverberating waves, which have not been described before in gyrencephalic brains, were also observed. Diffusion gradients created in the cortex surface (i.e., KCl concentrations), sulci, vessels and SD-SD interactions make the gyrencephalic brain prone to the appearance of irregular SD waves. CONCLUSION: The gyrencephalic brain is capable of irregular SD propagation patterns. The irregularities of the gyrencephalic brain cortex may promote the presence of re-entrance waves, such as spirals and reverberating waves.

Bridging the scales: semantic integration of quantitative SBML in graphical multi-cellular models and simulations with EPISIM and COPASI.

MOTIVATION: Biological reality can in silico only be comprehensively represented in multi-scaled models. To this end, cell behavioural models addressing the multi-cellular level have to be semantically linked with mechanistic molecular models. These requirements have to be met by flexible software workflows solving the issues of different time scales, inter-model variable referencing and flexible sub-model embedding. RESULTS: We developed a novel software workflow (EPISIM) for the semantic integration of Systems Biology Markup Language (SBML)-based quantitative models in multi-scaled tissue models and simulations. This workflow allows to import and access SBML-based models. SBML model species, reactions and parameters are semantically integrated in cell behavioural models (CBM) represented by graphical process diagrams. By this, cellular states like proliferation and differentiation can be flexibly linked to gene-regulatory or biochemical reaction networks. For a multi-scale agent-based tissue simulation executable code is automatically generated where different time scales of imported SBML models and CBM have been mapped. We demonstrate the capabilities of the novel software workflow by integrating Tyson's cell cycle model in our model of human epidermal tissue homeostasis. Finally, we show the semantic interplay of the different biological scales during tissue simulation. AVAILABILITY: The EPISIM platform is available as binary executables for Windows, Linux and Mac OS X at http://www.tiga.uni-hd.de. Supplementary data are available at http://www.tiga.uni-hd.de/supplements/SemSBMLIntegration.html. CONTACT: niels.grabe@bioquant.uni-heidelberg.de.

Computer-based analysis of general movements reveals stereotypies predicting cerebral palsy.

AIM: To evaluate a kinematic paradigm of automatic general movements analysis in comparison to clinical assessment in 3-month-old infants and its prediction for neurodevelopmental outcome. METHOD: Preterm infants at high risk (n=49; 26 males, 23 females) and term infants at low risk (n=18; eight males, 10 females) of developmental impairment were recruited from hospitals around Heidelberg, Germany. Kinematic analysis of general movements by magnet tracking and clinical video-based assessment of general movements were performed at 3 months of age. Neurodevelopmental outcome was evaluated at 2 years. By comparing the general movements of small samples of children with and without cerebral palsy (CP), we developed a kinematic paradigm typical for infants at risk of developing CP. We tested the validity of this paradigm as a tool to predict CP and neurodevelopmental impairment. RESULTS: Clinical assessment correctly identified almost all infants with neurodevelopmental impairment including CP, but did not predict if the infant would be affected by CP or not. The kinematic analysis, in particular the stereotypy score of arm movements, was an excellent predictor of CP, whereas stereotyped repetitive movements of the legs predicted any neurodevelopmental impairment. INTERPRETATION: The automatic assessment of the stereotypy score by magnet tracking in 3-month-old spontaneously moving infants at high risk of developmental abnormalities allowed a valid detection of infants affected and unaffected by CP.

Extraction of respiratory myogram interference from the ECG and its application to characterize sleep-related breathing disorders in atrial fibrillation.

BACKGROUND AND PURPOSE: Present methods to extract respiratory myogram interference (RMI) from the Holter-ECG and assess effect of supraventricular arrhythmias (SVAs) onto ECG-based detection of sleep-related breathing disorders (SRBDs) and AHI estimation. METHODS: RMI was quantified as residual energy after ECG cancellation or high-pass filtering for different windowing constellations. In 140 cases without (SET_A) and 10 cases with persistent SVAs (SET_B), respiratory polysomnogram annotations served as reference for SRDB detection from Holter-ECGs. We applied our previously published method to identify SRDBs in 1-min epochs and estimate the AHI based on joint modulations in RMI and QRS-area. RESULTS: Sensitivity and specificity of 0.855/0.860 in SET_A dropped to 0.831/0.75 in SET_B. A significantly higher number of wake events in SET_B likely contribute to the asymmetric decrease and is consistent with a tendency to overestimate the AHI. CONCLUSIONS: Despite reduced accuracy, RMI and QRS-area appear relatively robust against SVA and promise Holter-based detection at least of medium to severe SRBDs also in patients with SVAs.

Cortical spreading depression dynamics can be studied using intrinsic optical signal imaging in gyrencephalic animal cortex.

OBJECTIVE: The aim of this study was to co-record electrical changes using electrocorticography (ECoG) and blood volume changes using intrinsic optical signal (IOS) imaging during the induction, propagation, and termination of cortical spreading depolarizations (CSDs). METHODS: Anesthetized male swine were craniotomized and monitored over 16-20 h. A ten-contact electrode strip was placed on the cortex of one hemisphere for ECoG. An optical imaging recording was implemented using a camera with an optical bandpass filter (564 nm, FWHM:15 nm) and a full spectrum light source. CSDs were induced by mechanical and KCl stimulation. Co-occurrences of ECoG baseline shifts and blood volume changes around electrodes were identified. RESULTS: A mean of 3 CSDs per hour were induced, in a total of 4 swine during 80 h of recording. The propagation of the CSDs increased progressively over the monitoring time. IOS enabled us to clearly visualize the induction, propagation, and termination of CSDs with a spatial resolution within the sub-millimeter range. Every CSD recorded using ECoG could also be observed in IOS imaging, although some blood volume changes of CSDs were observed that terminated before reaching any of the ECoG electrodes. CONCLUSION: IOS imaging enables an in vivo evaluation of CSD dynamics over a large surface of gyrencephalic brain.

Femoral derotation osteotomy-Does intraoperative electromagnetic tracking reflect the dynamic outcome?

Femoral derotation osteotomy (FDO) is a well-established procedure for the correction of internal rotation gait in children with cerebral palsy. Various studies have demonstrated good results for FDO both in short-term and long-term evaluation with some describing recurrence and over- or under-corrections. The present study evaluates the use of an objective intraoperative derotation measurement through electromagnetic tracking. We report the static and dynamic results of 11 cases with internal rotation gait (8 male, 3 female, mean age 22.2 years), that underwent FDO with intraoperative electromagnetic tracking and conventional goniometric measurement of the correction. The dynamic and static changes were assessed through three-dimensional gait analysis after a mean of 12 months after surgery and rotational imaging preoperative and after a mean of eleven days postoperatively. Mean hip rotation in stance significantly decreased from 20.9° (SD 5.9) to 5.8° (SD 4.7°) after FDO. The mean amount of derotation quantified by electromagnetic tracking was 23.2° (16.5°-28.8°) and 25.1° (20.0°-33.0°) for goniometric measurement. Both measurement modalities showed small differences to rotational imaging (electromagnetic bone tracking [EMT]: 0.72°; goniometer: 1.19°) but a large deviation when compared to three-dimensional gait analysis (EMT: 8.5°, goniometer: 9.1°). In comparison to the static changes and EMT measurement, the dynamic changes measured during 3-D-gait analysis reflected only 66% of the actual derotation performed during surgery. Although electromagnetic tracking allows a precise intraoperative assessment of the derotation during FDO, the amount of intraoperative correction is not reflected in the improvements in three-dimensional gait analysis.

Spatial quantification and classification of skin response following perturbation using organotypic skin cultures.

MOTIVATION: For a mechanistic understanding of skin and its response to an induced perturbation, systems biology is gaining increasing attention. Unfortunately, quantitative and spatial expression data for skin, like for most other tissues, are almost not available. RESULTS: Integrating organotypic skin cultures, whole-slide scanning and subsequent image processing provides bioinformatics with a novel source of spatial expression data. We here used this approach to quantitatively describe the effect of treating organotypic skin cultures with sodium dodecyl sulphate in a non-corrosive concentration. We first measured the differentiation-related spatial expression gradient of Heat-Shock-Protein 27 in a time series of up to 24 h. Secondly, a multi-dimensional tissue classifier for predicting skin irritation was developed based on abstract features of these profiles. We obtained a high specificity of 0.94 and a sensitivity of 0.92 compared with manual classification. Our results demonstrate that the integration of tissue cultures, whole-slide scanning and image processing is well suited for both the standardized data acquisition for systems biological tissue models and a highly robust classification of tissue responses.

Quantitative myocardial blush grade for the detection of cardiac allograft vasculopathy.

BACKGROUND: Cardiac allograft vasculopathy (CAV) progressively compromises microvascular perfusion and function in heart transplantation (HTx)-recipients. The aim of our study was to investigate the ability of quantitative myocardial blush grade (MBG) to detect CAV. METHODS: In consecutive HTx-recipients (n = 72) who underwent surveillance cardiac catheterization, MBG was assessed visually and quantitatively, by analyzing the time course of contrast agent intensity rise. Hereby, the parameter G(max)/T(max) was calculated as the plateau of grey-level intensity (G(max)) divided by the time-to-peak intensity (T(max)). HTx-recipients and 18 healthy volunteers underwent cardiac magnetic resonance, to assess diastolic strain rates and myocardial perfusion reserve during pharmacologic hyperemia. RESULTS: Significant correlations were observed between G(max)/T(max) with perfusion reserve and with mean diastolic strain rates (r(2) = 0.68 and r(2) = 0.58, P < .001 for both). Visual and quantitative MBG using a cutoff value of G(max)/T(max) = 2.7/s yielded significantly higher accuracy than stenosis severity on coronary angiograms for the detection of impaired microvascular integrity as a surrogate marker for CAV (AUC = 0.78, SE = 0.06, 95% CI = 0.66-0.87 for lumen narrowing versus AUC = 0.91, SE = 0.03, 95%CI = 0.84-0.97 for G(max)/T(max); P < .01). Furthermore, quantitative MBG provided more robust prediction of survival (chi(2)= 14.0, P < .001), compared to visually estimated blush (chi(2)= 5.4, P = .02) and to coronary lumen narrowing assessment, (chi(2)= 4.8, P = .04). CONCLUSIONS: Quantification of MBG can be performed on coronary angiograms of HTx-recipients, and may help with the identification of early CAV in patients with impaired perfusion reserve but without angiographically evident atherosclerosis.

Modeling multi-cellular behavior in epidermal tissue homeostasis via finite state machines in multi-agent systems.

MOTIVATION: For the efficient application of multi-agent systems to spatial and functional modeling of tissues flexible and intuitive modeling tools are needed, which allow the graphical specification of cellular behavior in a tissue context without presuming specialized programming skills. RESULTS: We developed a graphical modeling system for multi-agent based simulation of tissue homeostasis. An editor allows the intuitive and hierarchically structured specification of cellular behavior. The models are then automatically compiled into highly efficient source code and dynamically linked to an interactive graphical simulation environment. The system allows the quantitative analysis of the morphological and functional tissue properties emerging from the cell behavioral model. We demonstrate the relevance of the approach using a recently published model of epidermal homeostasis as well as a series of cell-cycle models. AVAILABILITY: The complete software is available in binary executables for MS-Windows and Linux at tiga.uni-hd.de.

Robust gridding of TMAs after whole-slide imaging using template matching.

Tissue microarrays (TMAs) represent an important approach for the high-throughput cellular analysis of large numbers of tissue samples on one single slide in research related to diagnostics and oncology. Whole-slide imaging now enables full scanning and subsequent image analysis of such TMAs. In contrast to automatically spotted RNA microarrays, TMAs are fabricated manually and mechanically by arranging hundreds of tissue cores in a single paraffin block. This procedure frequently results in quality problems severely hampering the later automatic image analysis of TMAs after whole-slide imaging. We therefore set out to (a) determine the extent of these quality issues in exemplary TMAs and (b) to develop a robust gridding method to identify the logical position coordinates of each TMA core on a virtual TMA slide. We present the first robust method identifying these coordinates by shifting a template grid over all cores of the TMA (template matching) and thereby measuring in how far the grid matches a predefined list of cores on the virtual TMA Slide. Analysis of 20 TMAs from Breast Cancer as well as 40 Head-and-Neck Cancer showed that frequent TMA layout issues comprise low staining, debris, core displacement, nonuniform background, missing cores, and rotated subarrays. On this highly demanding test comprising chromogen as well as fluorescence stained TMAs, our template matching method achieved an excellent position analysis. Of 8900 cores, 8864 (99.59%) were assigned properly. In all 60 slides of the test set, no localization error occurred. The automatic grid analysis of TMAs after whole-slide imaging is highly demanding and requires dedicated algorithms. We demonstrate such a method and evaluate its performance. © 2010 International Society for Advancement of Cytometry.

Early assessment of infarct size and prediction of functional recovery by quantitative myocardial blush grade in patients with acute coronary syndromes treated according to current guidelines.

PURPOSE: To determine whether quantification of myocardial blush grade (MBG) during cardiac catheterization can aid the determination of follow-up left ventricular (LV)-function in patients with ST-elevation and non-ST-elevation myocardial infarction (STEMI and NSTEMI). METHODS: We prospectively examined patients with first STEMI (n = 46) and NSTEMI (n = 49). ECG-gated angiographic series were used to quantify MBG by analyzing the time course of contrast agent intensity rise. Hereby, the parameter G(max)/T(max) was calculated, derived from the plateau of grey-level intensity (G(max)), divided by the time-to-peak intensity (T(max)). Cardiac magnetic resonance imaging (CMR) deemed as the standard reference for the estimation of infarct size, transmurality and of the LV-function at 6 months of follow-up. RESULTS: Cut-off values of G(max)/T(max)=5.7/sec and 3.8/sec, respectively, yielded similar accuracy as infarct transmurality for the prediction of follow-up ejection fraction >55% (AUC = 0.86 for STEMI and AUC = 0.90 for NSTEMI, by G(max)/T(max) and AUC = 0.85 for STEMI and AUC = 0.89 for NSTEMI, by infarct transmurality, respectively, P = NS). Both clearly surpassed the predictive value of visual MBG (AUC = 0.69 for STEMI and AUC = 0.68 for NSTEMI, P < 0.05). CONCLUSION: G(max)/T(max) is an easy to acquire but highly valuable surrogate parameter for infarct size, which yields equally high accuracy with infarct transmurality and favorably compares with visually assessed blush grades for the prediction of follow-up LV-function in patients with acute ischemic syndromes.

Nuclear staining and relative distance for quantifying epidermal differentiation in biomarker expression profiling.

BACKGROUND: The epidermal physiology results from a complex regulated homeostasis of keratinocyte proliferation, differentiation and death and is tightly regulated by a specific protein expression during cellular maturation. Cellular in silico models are considered a promising and inevitable tool for the understanding of this complex system. Hence, we need to incorporate the information of the differentiation dependent protein expression in cell based systems biological models of tissue homeostasis. Such methods require measuring tissue differentiation quantitatively while correlating it with biomarker expression intensities. RESULTS: Differentiation of a keratinocyte is characterized by its continuously changing morphology concomitant with its movement from the basal layer to the surface, leading to a decreased average nuclei density throughout the tissue. Based thereon, we designed and evaluated three different mathematical measures (nuclei based, distance based, and joint approach) for quantifying differentiation in epidermal keratinocytes. We integrated them with an immunofluorescent staining and image analysis method for tissue sections, automatically quantifying epidermal differentiation and measuring the corresponding expression of biomarkers. When studying five well-known differentiation related biomarkers in an epidermal neck sample only the resulting biomarker profiles incorporating the relative distance information of cells to the tissue borders (distance based and joint approach) provided a high-resolution view on the whole process of keratinocyte differentiation. By contrast, the inverse nuclei density approach led to an increased resolution at early but heavily decreased resolution at late differentiation. This effect results from the heavy non-linear decay of DAPI intensity per area, probably caused by cytoplasmic growth and chromatin decondensation. In the joint approach this effect could be compensated again by incorporating distance information. CONCLUSION: We suppose that key mechanisms regulating tissue homeostasis probably depend more on distance information rather than on nuclei reorganization. Concluding, the distance approach appears well suited for comprehensively observing keratinocyte differentiation.

Reconstructing protein networks of epithelial differentiation from histological sections.

MOTIVATION: For systems biology of complex stratified epithelia like human epidermis, it will be of particular importance to reconstruct the spatiotemporal gene and protein networks regulating keratinocyte differentiation and homeostasis. RESULTS: Inside the epidermis, the differentiation state of individual keratinocytes is correlated with their respective distance from the connective tissue. We here present a novel method to profile this correlation for multiple epithelial protein biomarkers in the form of quantitative spatial profiles. Profiles were computed by applying image processing algorithms to histological sections stained with tri-color indirect immunofluorescence. From the quantitative spatial profiles, reflecting the spatiotemporal changes of protein expression during cellular differentiation, graphs of protein networks were reconstructed. CONCLUSION: Spatiotemporal networks can be used as a means for comparing and interpreting quantitative spatial protein expression profiles obtained from different tissue samples. In combination with automated microscopes, our new method supports the large-scale systems biological analysis of stratified epithelial tissues.

Quantification of the segmental kinematics of spontaneous infant movements.

This article introduces a method to capture the movements of the upper and the lower limb of infants using an electromagnetic tracking system and to reliably calculate the segmental kinematics. Analysis of the spontaneous movements of infants is important e.g. in the context of the "General Movement Analysis", which aims at the early diagnosis of motor dysfunctions. Due to special constraints regarding infant anatomy, previous approaches based on optical tracking could only gather position data of the infant' segments, whereas with this method in addition relative segment angles can be calculated. The spontaneous movements of the infant and simple calibration movements of the hand and the foot are used to calculate the joint centers and the joint axes of a multi-segmental chain model. The quality of the calibration movements is assessed at calibration time by calculating the root mean square deviation from the total least squares regression plane. The general accuracy of the recording is evaluated by the difference between recorded and estimated sensor positions and the difference between recorded and estimated sensor orientations. Movements of 20 infants between term and 3 months post term age were recorded and processed. A first application illustrates how abnormal movement patterns are manifested in the segmental kinematics. The results show that the presented method is a practicable and reliable way to record spontaneous infant movements and to calculate the segmental kinematics.

Precursors of syncope in linear and non-linear parameters of heart rate variability during pediatric head-up tilt test.

The aim of this study was to identify precursors of neurocardiogenic syncope (NCS) in ECG parameters of children and adolescents who undergo head-up tilt testing (HUTT). Established linear and non-linear parameters of heart rate variability (HRV) were calculated minute-by-minute in 44 young patients with an NCS history (age 7-20 years, 22 female, 22 male, positive HUTT) and 34 age-matched healthy controls (age 7-20 years, 17 female, 17 male, negative HUTT) during 60 degrees HUTT. The influence of age and gender on the response to tilting was studied using the Wilcoxon rank sum test. We also assessed the predictive power of individual features with respect to HUTT outcome within three temporal windows (0-2 min after tilt; 2-5 min after tilt, and 5-2 min before tilt-back) by means of receiver operating characteristics analysis. Our results indicate that prediction of HUTT outcome should be restricted to subjects in or after puberty. In this group, descriptors based on co-occurrence or joint-recurrence analysis in recurrence plots showed promising predictive power (up to 86% sensitivity and 90% specificity, area under the curve 0.91). Time-domain parameters (standard deviation of differences for successive RR intervals) reached 75% sensitivity and 80% specificity. We conclude that HRV analysis within the first 5 min after tilting provides significant information on HUTT outcome and may be useful in conjunction with more sophisticated classification strategies for shortening HUTT duration in subjects after puberty.

Confounding Factors in ECG-based Detection of Sleep-disordered Breathing.

OBJECTIVES: To assess the relevance of various potential confounding factors (comorbidities, obesity, body position, ECG lead, respiratory event type and sleep stage) on the detectability of sleep-related breathing disorders from the ECG. METHODS: A set of 140 simultaneous recordings of polysomnograms and 8-channel Holter ECGs taken from 121 patients with suspected sleep related breathing disorders is stratified with respect to the named factors. Minute-by-minute apnea detection performance is assessed using separate receiver operating characteristics curves for each of the subgroups. The detection is based on parameters of heart rate, ECG amplitude and respiratory myogram interference in the ECG. We consider spectral and correlation-based features. RESULTS: The results show that typical comorbidities and supine body position impede apnea detection from the heart rate. Availability of multiple ECG-leads improves the robustness of ECG amplitude based detection with respect to posture influence. But quite robust apnea detection is achievable with even a single ECG channel - preferably lead I. Sleep stages and respiratory event type have a significant and quite consistent effect on apnea detection sensitivity with better results for light sleep stages, and worse results for REM sleep. Mixed and obstructive events are better detected than central apneas and hypopneas. CONCLUSIONS: Various factors confound the detection of sleep apnea based on the ECG. These findings should be taken into account when comparing results obtained from different data sets and may help to understand limitations of current and to improve robustness of new detection algorithms.

Electromagnetic navigated condylar positioning after high oblique sagittal split osteotomy of the mandible: a guided method to attain pristine temporomandibular joint conditions.

OBJECTIVES: Reproduction of the exact preoperative proximal-mandible position after osteotomy in orthognathic surgery is difficult to achieve. This clinical pilot study evaluated an electromagnetic (EM) navigation system for condylar positioning after high-oblique sagittal split osteotomy (HSSO). STUDY DESIGN: After HSSO as part of 2-jaw surgery, the position of 10 condyles was intraoperatively guided by an EM navigation system. As controls, 10 proximal segments were positioned by standard manual replacement. Accuracy was measured by pre- and postoperative cone beam computed tomography imaging. RESULTS: Overall, EM condyle repositioning was equally accurate compared with manual repositioning (P > .05). Subdivided into 3 axes, significant differences could be identified (P < .05). Nevertheless, no significantly and clinically relevant dislocations of the proximal segment of either the EM or the manual repositioning method could be shown (P > .05). CONCLUSIONS: This pilot study introduces a guided method for proximal segment positioning after HSSO by applying the intraoperative EM system. The data demonstrate the high accuracy of EM navigation, although manual replacement of the condyles could not be surpassed. However, EM navigation can avoid clinically hidden, severe malpositioning of the condyles.

A flexible registration and evaluation engine (f.r.e.e.).

We present an image registration framework which offers effective assistance for solving current registration problems. This work was motivated by the huge amount of registration problems in clinical applications and the problem of finding adequate solutions and properly comparing them. We have therefore designed a framework that supports the establishment, evaluation and comparison of registration approaches. Flexible registration and evaluation engine (f.r.e.e.) achieves a broad basis of algorithms by utilizing the insight segmentation and registration toolkit (ITK). This basis can be extended by virtually any new approach or algorithm, which then becomes seamlessly integrated into the method set of the f.r.e.e. framework. The framework offers suitable tools for an easy integration, optimization and proper evaluation of registration approaches, as well as an efficient utilization of the results in clinical routine. The framework is currently being evaluated at the Heidelberg University Hospital, Germany. The first results were gathered with an application implemented for the Neurosurgical Department of the hospital. In these tests the framework concept, along with its specific tools, was very promising for establishing clinical applications (e.g. preoperative neurosurgical planning; registration of cardiac images) and therefore motivated further development. The ability to automatically optimize the parameterization of registration methods regarding a given test set also proved useful, allowing more concentration on scientific problems themselves and not on the laborious task of parameter tweaking. Due to implemented abstraction layers, f.r.e.e. also allows a high degree of transparency and thus good comparability of registration approaches and results.

Quantification of myocardial perfusion for CAD diagnosis.

We introduce a computer based algorithm for objective quantification of myocardial perfusion to support the diagnosis of cad patients. This new method is based on conventional cine angiographic films. In order to achieve maximal quality of the digital subtraction angiography images, the sequence is synchronized with the ECG. Optionally, the digital images can be motion compensated by a two step matching method. The spatio-temporal spread of blood, or the so-called blush, through the microvasculature to the myocardium--indicated by dye injection--represents a characteristic pattern for the myocardial perfusion. This dynamic temporal pattern is characterized by typical features as the maximal value of blush intensity, of increase and of decrease velocity which correspond with the different phases of flooding in and washout. On the basis of 100 different temporal blush profiles, an algorithm is established which classifies the acquired blush patterns into 4 different grades.