A novel activated-zinc antiseptic solution effective against MRSA and Pseudomonas aeruginosa: a pig model.

OBJECTIVE: The purpose of this study was to investigate the antimicrobial efficacy of a novel activated zinc solution against meticillin-resistant Staphylococcus aureus (MRSA) and Pseudomonas aeruginosa after one hour, and to evaluate any untoward effect of the solution on local wound tissue at 24 hours after solution exposure in a pig wound model. METHOD: A pathogen-free, commercially raised, Yorkshire-cross female pig was acquired 12 days prior to the procedure. Within one week prior to the procedure, a small loopful of test bacteria, Pseudomonas aeruginosa (pig-isolate) and MRSA (ATCC-6538), were streaked and cultured on a non-selective agar. Full-thickness wounds (n=24) were created and evenly divided into three groups: control wounds (exposed to bacteria but untreated, n=8); wounds treated with Compound 1 (n=8), and wounds treated with Compound 2 (n=8). All wounds were dressed and monitored for one hour and 24 hours. RESULTS: After one hour, the wounds treated with Compound 1 and Compound 2 had a mean recoverable total bacteria of 2.8 log colony forming units (CFUs) and 3.5 logCFUs, respectively. After one hour, the wounds treated with Compound 1 and Compound 2 had a mean recoverable MRSA of 2.3 logCFUs and 1.6 logCFUs, respectively (p=0.009). After one hour, the wounds treated with Compound 1 and Compound 2 had a mean recoverable Pseudomonas aeruginosa of 0.3 logCFUs and 0.0 logCFUs, respectively (p=0.000). After 24 hours of exposure to Compound 1 and Compound 2, there was no statistically significant increased necrosis (p=0.12, p=0.31, respectively) or neutrophilic infiltrate (Compound 2, p=0.12) when compared with control wounds. CONCLUSION: The novel activated-zinc compound used in this study demonstrated a 99.5-99.9% reduction in total bacteria, a 99.9-99.98% reduction in MRSA, and 100% eradication of Pseudomonas aeruginosa one hour after exposure. This novel solution may provide another significant tool to treat and/or prevent wound infections.

Metadata Framework to Support Deployment of Digital Health Technologies in Clinical Trials in Parkinson's Disease.

Sensor data from digital health technologies (DHTs) used in clinical trials provides a valuable source of information, because of the possibility to combine datasets from different studies, to combine it with other data types, and to reuse it multiple times for various purposes. To date, there exist no standards for capturing or storing DHT biosensor data applicable across modalities and disease areas, and which can also capture the clinical trial and environment-specific aspects, so-called metadata. In this perspectives paper, we propose a metadata framework that divides the DHT metadata into metadata that is independent of the therapeutic area or clinical trial design (concept of interest and context of use), and metadata that is dependent on these factors. We demonstrate how this framework can be applied to data collected with different types of DHTs deployed in the WATCH-PD clinical study of Parkinson's disease. This framework provides a means to pre-specify and therefore standardize aspects of the use of DHTs, promoting comparability of DHTs across future studies.

A Novel Activated Zinc Solution with Improved Efficacy Against Pseudomonas and MRSA Biofilm Compared to Chlorhexidine and Povidone-Iodine.

INTRODUCTION: The search for the optimal agent for infection eradication in periprosthetic joint infection (PJI) remains challenging as there are limited efficacious and safe options. The ideal solution should have significant bactericidal and anti-biofilm activity to be able to eradicate infection with the preservation of prosthetic components. Therefore, the purpose of this study was to 1) investigate the anti-biofilm efficacy of a novel activated zinc solution against Pseudomonas aeruginosa and methicillin-resistant Staphylococcus aureus (MRSA) biofilm in vitro and 2) compare its efficacy against two leading commercially available antimicrobial irrigants (CHG and 0.35% povidone-iodine [PI]). MATERIALS AND METHODS: A modified Robbins device (MRD) was utilized to replicate Pseudomonas aeruginosa and MRSA biofilms. The primary outcome was to determine bacterial reduction after two hours of biofilm exposure to an activated zinc solution, CHG, and PI, and compare to untreated controls. RESULTS: Against Pseudomonas biofilm, activated zinc demonstrated a 4.5-log (99.996%) reduction, chlorhexidine demonstrated a 0.9-log (87.4%) reduction (p<0.001), and PI demonstrated a 0.8-log (83.1%) reduction (p<0.001). After two hours of exposure, activated zinc had undetectable MRSA with a 7.08-log (100%) reduction, chlorhexidine had a 1.9-log (98.7%) reduction (p<0.01), and PI had a 3.2-log (99.9%) reduction (p<0.01). CONCLUSIONS: Our novel activated zinc compound demonstrated a 99.996% reduction in Pseudomonas biofilm and a 100% reduction in MRSA biofilm. This novel solution may provide a significant tool in the arsenal to treat and/or prevent PJI and other wound infections. Future in vivo studies are warranted to demonstrate clinical utility, efficacy, and safety.

A standard system phantom for magnetic resonance imaging.

PURPOSE: A standard MRI system phantom has been designed and fabricated to assess scanner performance, stability, comparability and assess the accuracy of quantitative relaxation time imaging. The phantom is unique in having traceability to the International System of Units, a high level of precision, and monitoring by a national metrology institute. Here, we describe the phantom design, construction, imaging protocols, and measurement of geometric distortion, resolution, slice profile, signal-to-noise ratio (SNR), proton-spin relaxation times, image uniformity and proton density. METHODS: The system phantom, designed by the International Society of Magnetic Resonance in Medicine ad hoc committee on Standards for Quantitative MR, is a 200 mm spherical structure that contains a 57-element fiducial array; two relaxation time arrays; a proton density/SNR array; resolution and slice-profile insets. Standard imaging protocols are presented, which provide rapid assessment of geometric distortion, image uniformity, T1 and T2 mapping, image resolution, slice profile, and SNR. RESULTS: Fiducial array analysis gives assessment of intrinsic geometric distortions, which can vary considerably between scanners and correction techniques. This analysis also measures scanner/coil image uniformity, spatial calibration accuracy, and local volume distortion. An advanced resolution analysis gives both scanner and protocol contributions. SNR analysis gives both temporal and spatial contributions. CONCLUSIONS: A standard system phantom is useful for characterization of scanner performance, monitoring a scanner over time, and to compare different scanners. This type of calibration structure is useful for quality assurance, benchmarking quantitative MRI protocols, and to transition MRI from a qualitative imaging technique to a precise metrology with documented accuracy and uncertainty.

Quantitative magnetic resonance imaging phantoms: A review and the need for a system phantom.

The MRI community is using quantitative mapping techniques to complement qualitative imaging. For quantitative imaging to reach its full potential, it is necessary to analyze measurements across systems and longitudinally. Clinical use of quantitative imaging can be facilitated through adoption and use of a standard system phantom, a calibration/standard reference object, to assess the performance of an MRI machine. The International Society of Magnetic Resonance in Medicine AdHoc Committee on Standards for Quantitative Magnetic Resonance was established in February 2007 to facilitate the expansion of MRI as a mainstream modality for multi-institutional measurements, including, among other things, multicenter trials. The goal of the Standards for Quantitative Magnetic Resonance committee was to provide a framework to ensure that quantitative measures derived from MR data are comparable over time, between subjects, between sites, and between vendors. This paper, written by members of the Standards for Quantitative Magnetic Resonance committee, reviews standardization attempts and then details the need, requirements, and implementation plan for a standard system phantom for quantitative MRI. In addition, application-specific phantoms and implementation of quantitative MRI are reviewed. Magn Reson Med 79:48-61, 2018. © 2017 International Society for Magnetic Resonance in Medicine.

Design, operation, and safety of single-room interventional MRI suites: practical experience from two centers.

The design and operation of a facility in which a magnetic resonance imaging (MRI) scanner is incorporated into a room used for surgical or endovascular cardiac interventions presents several challenges. MR safety must be maintained in the presence of a much wider variety of equipment than is found in a diagnostic unit, and of staff unfamiliar with the MRI environment, without compromising the safety and practicality of the interventional procedure. Both the MR-guided cardiac interventional unit at Kings College London and the intraoperative imaging suite at the National Hospital for Neurology and Neurosurgery are single-room interventional facilities incorporating 1.5 T cylindrical-bore MRI scanners. The two units employ similar strategies to maintain MR safety, both in original design and day-to-day operational workflows, and between them over a decade of incident-free practice has been accumulated. This article outlines these strategies, highlighting both similarities and differences between the units, as well as some lessons learned and resulting procedural changes made in both units since installation.

Coalition Against Major Diseases/European Medicines Agency biomarker qualification of hippocampal volume for enrichment of clinical trials in predementia stages of Alzheimer's disease.

BACKGROUND: Regulatory qualification of a biomarker for a defined context of use provides scientifically robust assurances to sponsors and regulators that accelerate appropriate adoption of biomarkers into drug development. METHODS: The Coalition Against Major Diseases submitted a dossier to the Scientific Advice Working Party of the European Medicines Agency requesting a qualification opinion on the use of hippocampal volume as a biomarker for enriching clinical trials in subjects with mild cognitive impairment, incorporating a scientific rationale, a literature review and a de novo analysis of Alzheimer's Disease Neuroimaging Initiative data. RESULTS: The literature review and de novo analysis were consistent with the proposed context of use, and the Committee for Medicinal Products for Human Use released an opinion in November 2011. CONCLUSIONS: We summarize the scientific rationale and the data that supported the first qualification of an imaging biomarker by the European Medicines Agency.

AI in imaging: the regulatory landscape.

Artificial intelligence (AI) methods have been applied to medical imaging for several decades, but in the last few years, the number of publications and the number of AI-enabled medical devices coming on the market have significantly increased. While some AI-enabled approaches are proving very valuable, systematic reviews of the AI imaging field identify significant weaknesses in a significant proportion of the literature. Medical device regulators have recently become more proactive in publishing guidance documents and recognizing standards that will require that the development and validation of AI-enabled medical devices need to be more rigorous than required for tradition "rule-based" software. In particular, developers are required to better identify and mitigate risks (such as bias) that arise in AI-enabled devices, and to ensure that the devices are validated in a realistic clinical setting to ensure their output is clinically meaningful. While this evolving regulatory landscape will mean that device developers will take longer to bring novel AI-based medical imaging devices to market, such additional rigour is necessary to address existing weaknesses in the field and ensure that patients and healthcare professionals can trust AI-enabled devices. There would also be benefits in the academic community taking into account this regulatory framework, to improve the quality of the literature and make it easier for academically developed AI tools to make the transition to medical devices that impact healthcare.

Understanding patterns of fatigue in health and disease: protocol for an ecological momentary assessment study using digital technologies.

INTRODUCTION: Fatigue is prevalent across a wide range of medical conditions and can be debilitating and distressing. It is likely that fatigue is experienced differently according to the underlying aetiology, but this is poorly understood. Digital health technologies present a promising approach to give new insights into fatigue.The aim of this study is to use digital health technologies, real-time self-reports and qualitative interview data to investigate how fatigue is experienced over time in participants with myeloma, long COVID, heart failure and in controls without problematic fatigue. Objectives are to understand which sensed parameters add value to the characterisation of fatigue and to determine whether study processes are feasible, acceptable and scalable. METHODS AND ANALYSIS: An ecological momentary assessment study will be carried out over 2 or 4 weeks (participant defined). Individuals with fatigue relating to myeloma (n=10), heart failure (n=10), long COVID (n=10) and controls without problematic fatigue or a study condition (n=10) will be recruited. ECG patches will measure heart rate variability, respiratory rate, body temperature, activity and posture. A wearable bracelet accompanied by environment beacons will measure physical activity, sleep and room location within the home. Self-reports of mental and physical fatigue will be collected via smartphone app four times daily and on-demand. Validated fatigue and affect questionnaires will be completed at baseline and at 2 weeks. End-of-study interviews will investigate experiences of fatigue and study participation. A feedback session will be offered to participants to discuss their data.Data will be analysed using multilevel modelling and machine learning. Interviews and feedback sessions will be analysed using content or thematic analyses. ETHICS AND DISSEMINATION: This study was approved by the East of England-Cambridge East Research Ethics Committee (22/EE/0261). The results will be disseminated in peer-reviewed journals and at international conferences. TRIAL REGISTRATION NUMBER: NCT05622669.

Identifying and characterising sources of variability in digital outcome measures in Parkinson's disease.

Smartphones and wearables are widely recognised as the foundation for novel Digital Health Technologies (DHTs) for the clinical assessment of Parkinson's disease. Yet, only limited progress has been made towards their regulatory acceptability as effective drug development tools. A key barrier in achieving this goal relates to the influence of a wide range of sources of variability (SoVs) introduced by measurement processes incorporating DHTs, on their ability to detect relevant changes to PD. This paper introduces a conceptual framework to assist clinical research teams investigating a specific Concept of Interest within a particular Context of Use, to identify, characterise, and when possible, mitigate the influence of SoVs. We illustrate how this conceptual framework can be applied in practice through specific examples, including two data-driven case studies.

Steps to standardization and validation of hippocampal volumetry as a biomarker in clinical trials and diagnostic criterion for Alzheimer's disease.

BACKGROUND: The promise of Alzheimer's disease biomarkers has led to their incorporation in new diagnostic criteria and in therapeutic trials; however, significant barriers exist to widespread use. Chief among these is the lack of internationally accepted standards for quantitative metrics. Hippocampal volumetry is the most widely studied quantitative magnetic resonance imaging measure in Alzheimer's disease and thus represents the most rational target for an initial effort at standardization. METHODS AND RESULTS: The authors of this position paper propose a path toward this goal. The steps include the following: (1) Establish and empower an oversight board to manage and assess the effort, (2) adopt the standardized definition of anatomic hippocampal boundaries on magnetic resonance imaging arising from the European Alzheimer's Disease Centers-Alzheimer's Disease Neuroimaging Initiative hippocampal harmonization effort as a reference standard, (3) establish a scientifically appropriate, publicly available reference standard data set based on manual delineation of the hippocampus in an appropriate sample of subjects (Alzheimer's Disease Neuroimaging Initiative), and (4) define minimum technical and prognostic performance metrics for validation of new measurement techniques using the reference standard data set as a benchmark. CONCLUSIONS: Although manual delineation of the hippocampus is the best available reference standard, practical application of hippocampal volumetry will require automated methods. Our intent was to establish a mechanism for credentialing automated software applications to achieve internationally recognized accuracy and prognostic performance standards that lead to the systematic evaluation and then widespread acceptance and use of hippocampal volumetry. The standardization and assay validation process outlined for hippocampal volumetry was envisioned as a template that could be applied to other imaging biomarkers.

Issues with threshold masking in voxel-based morphometry of atrophied brains.

There is great interest in using automatic computational neuroanatomy tools to study ageing and neurodegenerative disease. Voxel-based morphometry (VBM) is one of the most widely used of such techniques. VBM performs voxel-wise statistical analysis of smoothed spatially normalised segmented Magnetic Resonance Images. There are several reasons why the analysis should include only voxels within a certain mask. We show that one of the most commonly used strategies for defining this mask runs a major risk of excluding from the analysis precisely those voxels where the subjects' brains were most vulnerable to atrophy. We investigate the issues related to mask construction, and recommend the use of alternative strategies which greatly decrease this danger of false negatives.

Analysis of serial magnetic resonance images of mouse brains using image registration.

The aim of this paper is to investigate techniques that can identify and quantify cross-sectional differences and longitudinal changes in vivo from magnetic resonance images of murine models of brain disease. Two different approaches have been compared. The first approach is a segmentation-based approach: Each subject at each time point is automatically segmented into a number of anatomical structures using atlas-based segmentation. This allows cross-sectional and longitudinal analyses of group differences on a structure-by-structure basis. The second approach is a deformation-based approach: Longitudinal changes are quantified by the registration of each subject's follow-up images to that subject's baseline image. In addition the baseline images can be registered to an atlas allowing voxel-wise analysis of cross-sectional differences between groups. Both approaches have been tested on two groups of mice: A transgenic model of Alzheimer's disease and a wild-type background strain, using serial imaging performed over the age range from 6-14 months. We show that both approaches are able to identify longitudinal and cross-sectional differences. However, atlas-based segmentation suffers from the inability to detect differences across populations and across time in regions which are much smaller than the anatomical regions. In contrast to this, the deformation-based approach can detect statistically significant differences in highly localized areas.

Comparison of phantom and registration scaling corrections using the ADNI cohort.

Rates of brain atrophy derived from serial magnetic resonance (MR) studies may be used to assess therapies for Alzheimer's disease (AD). These measures may be confounded by changes in scanner voxel sizes. For this reason, the Alzheimer's Disease Neuroimaging Initiative (ADNI) included the imaging of a geometric phantom with every scan. This study compares voxel scaling correction using a phantom with correction using a 9 degrees of freedom (9DOF) registration algorithm. We took 129 pairs of baseline and 1-year repeat scans, and calculated the volume scaling correction, previously measured using the phantom. We used the registration algorithm to quantify any residual scaling errors, and found the algorithm to be unbiased, with no significant (p=0.97) difference between control (n=79) and AD subjects (n=50), but with a mean (SD) absolute volume change of 0.20 (0.20) % due to linear scalings. 9DOF registration was shown to be comparable to geometric phantom correction in terms of the effect on atrophy measurement and unbiased with respect to disease status. These results suggest that the additional expense and logistic effort of scanning a phantom with every patient scan can be avoided by registration-based scaling correction. Furthermore, based upon the atrophy rates in the AD subjects in this study, sample size requirements would be approximately 10-12% lower with (either) correction for voxel scaling than if no correction was used.

Publication rate of abstracts presented at the shoulder and elbow session of the American Academy of Orthopaedic Surgery.

Many shoulder and elbow abstracts presented at the American Academy of Orthopaedic Surgeons (AAOS) annual meeting are cited in the orthopaedic literature or are used to guide orthopaedic practice, but not all of these abstracts are submitted, survive peer review, or eventually are published. Presuming unpublished works have not been scientifically confirmed, one could question whether it is academically responsible to cite abstracts presented at the AAOS before they are peer-reviewed and published. To partly address this issue we determined the peer-reviewed publication rate for 558 abstracts (233 papers and 325 posters) presented at the shoulder and elbow sessions of the AAOS from 1999 to 2004. In April 2007, we searched the computerized database MEDLINE and PubMed for published articles based on these abstracts. We examined the published articles to assess publication rate, time to publication, change in contents, change in authors, and change in conclusions of abstracts. The overall publication rate in peer-reviewed journals was 58% (321 of 558), similar to other orthopaedic meetings and medical disciplines. We believe it is unacceptable to cite shoulder and elbow abstracts submitted to the AAOS because only slightly more than (1/2) (58%) of them are authenticated scientifically.

Accuracy assessment of global and local atrophy measurement techniques with realistic simulated longitudinal Alzheimer's disease images.

The evaluation of atrophy quantification methods based on magnetic resonance imaging have been usually hindered by the lack of realistic gold standard data against which to judge these methods or to help refine them. Recently [Camara, O., Schweiger, M., Scahill, R., Crum, W., Sneller, B., Schnabel, J., Ridgway, G., Cash, D., Hill, D., Fox, N., 2006. Phenomenological model of diffuse global and regional atrophy using finite-element methods. IEEE Trans. Med.l Imaging 25, 1417-1430], we presented a technique in which atrophy is realistically simulated in different tissue compartments or neuroanatomical structures with a phenomenological model. In this study, we have generated a cohort of realistic simulated Alzheimer's disease (AD) images with known amounts of atrophy, mimicking a set of 19 real controls and 27 probable AD subjects, with an improved version of our atrophy simulation methodology. This database was then used to assess the accuracy of several well-known computational anatomy methods which provide global (BSI and SIENA) or local (Jacobian integration) estimates of longitudinal atrophy in brain structures using MR images. SIENA and BSI results correlated very well with gold standard data (Pearson coefficient of 0.962 and 0.969 respectively), achieving small mean absolute differences with respect to the gold standard (percentage change from baseline volume): BSI of 0.23%+/-0.26%; SIENA of 0.22%+/-0.28%. Jacobian integration was guided by both fluid and FFD-based registration techniques and resulting deformation fields and associated Jacobians were compared, region by region, with gold standard ones. The FFD-based technique outperformed the fluid one in all evaluated structures (mean absolute differences from the gold standard in percentage change from baseline volume): whole brain, FFD=0.31%, fluid=0.58%; lateral ventricles, FFD=0.79%; fluid=1.45%; left hippocampus, FFD=0.82%; fluid=1.42%; right hippocampus, FFD=0.95%; fluid=1.62%. The largest errors for both local techniques occurred in the sulcal CSF (FFD=2.27%; fluid=3.55%) regions. For large structures such as the whole brain, these mean absolute differences, relative to the applied atrophy, represented similar percentages for the BSI, SIENA and FFD techniques (controls/patients): BSI, 51.99%/16.36%; SIENA, 62.34%/21.59%; FFD, 41.02%/24.95%. For small structures such as the hippocampi, these percentages were larger, especially for controls where errors were approximately equal to the small applied changes (controls/patients): FFD, 92.82%/43.61%. However, these apparently large relative errors have not prevented the global or hippocampal measures from finding significant group separation in our study. The evaluation framework presented here will help in quantifying whether the accuracy of future methodological developments is sufficient for analysing change in smaller or less atrophied local brain regions. Results obtained in our experiments with realistic simulated data confirm previously published estimates of accuracy for both evaluated global techniques. Regarding Jacobian Integration methods, the FFD-based one demonstrated promising results and potential for being used in clinical studies alongside (or in place of) the more common global methods. The generated gold standard data has also allowed us to identify some stages and sets of parameters in the evaluated techniques--the brain extraction step in the global techniques and the number of multi-resolution levels and the stopping criteria in the registration-based methods--that are critical for their accuracy.

Correction of misaligned slices in multi-slice cardiovascular magnetic resonance using slice-to-volume registration.

A popular technique to reduce respiratory motion for cardiovascular magnetic resonance is to perform a multi-slice acquisition in which a patient holds their breath multiple times during the scan. The feasibility of rigid slice-to-volume registration to correct for misalignments of slice stacks in such images due to differing breath-hold positions is explored. Experimental results indicate that slice-to-volume registration can compensate for the typical misalignments expected. Correction of slice misalignment results in anatomically more correct images, as well as improved left ventricular volume measurements. The interstudy reproducibility has also been improved reducing the number of samples needed for cardiac MR studies.

Quantitative evaluation of free-form deformation registration for dynamic contrast-enhanced MR mammography.

In this paper, we present an evaluation study of a set of registration strategies for the alignment of sequences of 3D dynamic contrast-enhanced magnetic resonance breast images. The accuracy of the optimal registration strategies was determined on unseen data. The evaluation is based on the simulation of physically plausible breast deformations using finite element methods and on contrast-enhanced image pairs without visually detectable motion artifacts. The configuration of the finite element model was chosen according to its ability to predict in vivo breast deformations for two volunteers. We computed transformations for ten patients with 12 simulated deformations each. These deformations were applied to the postcontrast image to model patient motion occurring between pre- and postcontrast image acquisition. The original precontrast images were registered to the corresponding deformed postcontrast images. The performance of several registration configurations (rigid, affine, B-spline based nonrigid, single-resolution, multi-resolution, and volume-preserving) was optimized for five of the ten patients. The images were most accurately aligned with volume-preserving single-resolution nonrigid registration employing 40 or 20 mm control point spacing. When tested on the remaining five patients the optimal configurations reduced the average mean registration error from 1.40 to 0.45 mm for the whole breast tissue and from 1.20 to 0.32 mm for the enhancing lesion. These results were obtained on average within 26 (81) min for 40 (20) mm control point spacing. The visual appearance of the difference images from 30 patients was significantly improved after 20 mm volume-preserving single-resolution nonrigid registration in comparison to no registration or rigid registration. No substantial volume changes within the region of the enhancing lesions were introduced by this nonrigid registration.

Factors influencing the accuracy of biomechanical breast models.

Recently it has been suggested that finite element methods could be used to predict breast deformations in a number of applications, including comparison of multimodality images, validation of image registration and image guided interventions. Unfortunately knowledge of the mechanical properties of breast tissues is limited. This study evaluated the accuracy with which biomechanical breast models based on finite element methods can predict the displacements of tissue within the breast in the practical clinical situation where the boundaries of the organ might be known reasonably accurately but there is some uncertainty on the mechanical properties of the tissue. For two datasets, we investigate the influence of tissue elasticity values, Poisson's ratios, boundary conditions, finite element solvers and mesh resolutions. Magnetic resonance images were acquired before and after compressing each volunteer's breast by about 20%. Surface displacement boundary conditions were derived from a three-dimensional nonrigid image registration. Six linear and three nonlinear elastic material models with and without skin were tested. These were compared to hyperelastic models. The accuracy of the models was evaluated by assessing the ability of the model to predict the location of 12 corresponding anatomical landmarks. The accuracy was most sensitive to the Poisson's ratio and the boundary condition. Best results were achieved for accurate boundary conditions, appropriate Poisson's ratios and models where fibroglandular tissue was at most four times stiffer than fatty tissue. These configurations reduced the mean (maximum) distance of the landmarks from 6.6 mm (12.4 mm) to 2.1 mm (3.4 mm) averaged over all experiments.

Generalized overlap measures for evaluation and validation in medical image analysis.

Measures of overlap of labelled regions of images, such as the Dice and Tanimoto coefficients, have been extensively used to evaluate image registration and segmentation algorithms. Modern studies can include multiple labels defined on multiple images yet most evaluation schemes report one overlap per labelled region, simply averaged over multiple images. In this paper, common overlap measures are generalized to measure the total overlap of ensembles of labels defined on multiple test images and account for fractional labels using fuzzy set theory. This framework allows a single "figure-of-merit" to be reported which summarises the results of a complex experiment by image pair, by label or overall. A complementary measure of error, the overlap distance, is defined which captures the spatial extent of the nonoverlapping part and is related to the Hausdorff distance computed on grey level images. The generalized overlap measures are validated on synthetic images for which the overlap can be computed analytically and used as similarity measures in nonrigid registration of three-dimensional magnetic resonance imaging (MRI) brain images. Finally, a pragmatic segmentation ground truth is constructed by registering a magnetic resonance atlas brain to 20 individual scans, and used with the overlap measures to evaluate publicly available brain segmentation algorithms.