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Target volume delineation is a vital but time-consuming and challenging part of radiotherapy, where the goal is to deliver sufficient dose to the target while reducing risks of side effects. For head and neck cancer (HNC) this is complicated by the complex anatomy of the head and neck region and the proximity of target volumes to organs at risk. The purpose of this study was to compare and evaluate conventional PET thresholding methods, six classical machine learning algorithms and a 2D U-Net convolutional neural network (CNN) for automatic gross tumor volume (GTV) segmentation of HNC in PET/CT images. For the latter two approaches the impact of single versus multimodality input on segmentation quality was also assessed. 197 patients were included in the study. The cohort was split into training and test sets (157 and 40 patients, respectively). Five-fold cross-validation was used on the training set for model comparison and selection. Manual GTV delineations represented the ground truth. Tresholding, classical machine learning and CNN segmentation models were ranked separately according to the cross-validation Sørensen-Dice similarity coefficient (Dice). PET thresholding gave a maximum mean Dice of 0.62, whereas classical machine learning resulted in maximum mean Dice scores of 0.24 (CT) and 0.66 (PET; PET/CT). CNN models obtained maximum mean Dice scores of 0.66 (CT), 0.68 (PET) and 0.74 (PET/CT). The difference in cross-validation Dice between multimodality PET/CT and single modality CNN models was significant (p ≤ 0.0001). The top-ranked PET/CT-based CNN model outperformed the best-performing thresholding and classical machine learning models, giving significantly better segmentations in terms of cross-validation and test set Dice, true positive rate, positive predictive value and surface distance-based metrics (p ≤ 0.0001). Thus, deep learning based on multimodality PET/CT input resulted in superior target coverage and less inclusion of surrounding normal tissue.

Background: Non-linear Bayesian genomic prediction models such as BayesA/B/C/R involve iteration and mostly Markov chain Monte Carlo (MCMC) algorithms, which are computationally expensive, especially when whole-genome sequence (WGS) data are analyzed. Singular value decomposition (SVD) of the genotype matrix can facilitate genomic prediction in large datasets, and can be used to estimate marker effects and their prediction error variances (PEV) in a computationally efficient manner. Here, we developed, implemented, and evaluated a direct, non-iterative method for the estimation of marker effects for the BayesC genomic prediction model., Methods: The BayesC model assumes a priori that markers have normally distributed effects with probability [Formula: see text] and no effect with probability (1 - [Formula: see text]). Marker effects and their PEV are estimated by using SVD and the posterior probability of the marker having a non-zero effect is calculated. These posterior probabilities are used to obtain marker-specific effect variances, which are subsequently used to approximate BayesC estimates of marker effects in a linear model. A computer simulation study was conducted to compare alternative genomic prediction methods, where a single reference generation was used to estimate marker effects, which were subsequently used for 10 generations of forward prediction, for which accuracies were evaluated., Results: SVD-based posterior probabilities of markers having non-zero effects were generally lower than MCMC-based posterior probabilities, but for some regions the opposite occurred, resulting in clear signals for QTL-rich regions. The accuracies of breeding values estimated using SVD- and MCMC-based BayesC analyses were similar across the 10 generations of forward prediction. For an intermediate number of generations (2 to 5) of forward prediction, accuracies obtained with the BayesC model tended to be slightly higher than accuracies obtained using the best linear unbiased prediction of SNP effects (SNP-BLUP model). When reducing marker density from WGS data to 30 K, SNP-BLUP tended to yield the highest accuracies, at least in the short term., Conclusions: Based on SVD of the genotype matrix, we developed a direct method for the calculation of BayesC estimates of marker effects. Although SVD- and MCMC-based marker effects differed slightly, their prediction accuracies were similar. Assuming that the SVD of the marker genotype matrix is already performed for other reasons (e.g. for SNP-BLUP), computation times for the BayesC predictions were comparable to those of SNP-BLUP.

Background: Tumour delineation is a challenging, time-consuming and complex part of radiotherapy planning. In this study, an automatic method for delineating locally advanced cervical cancers was developed using a machine learning approach., Materials and Methods: A method for tumour segmentation based on image voxel classification using Fisher?s Linear Discriminant Analysis (LDA) was developed. This was applied to magnetic resonance (MR) images of 78 patients with locally advanced cervical cancer. The segmentation was based on multiparametric MRI consisting of T2- weighted (T2w), T1-weighted (T1w) and dynamic contrast-enhanced (DCE) sequences, and included intensity and spatial information from the images. The model was trained and assessed using delineations made by two radiologists., Results: Segmentation based on T2w or T1w images resulted in mean sensitivity and specificity of 94% and 52%, respectively. Including DCE-MR images improved the segmentation model?s performance significantly, giving mean sensitivity and specificity of 85?93%. Comparisons with radiologists? tumour delineations gave Dice similarity coefficients of up to 0.44., Conclusion: Voxel classification using a machine learning approach is a flexible and fully automatic method for tumour delineation. Combining all relevant MR image series resulted in high sensitivity and specificity. Moreover, the presented method can be extended to include additional imaging modalities.

Background: Dairy products account for approximately 60% of the iodine intake in the Norwegian population. The iodine concentration in cow's milk varies considerably, depending on feeding practices, season, and amount of iodine and rapeseed products in cow fodder. The variation in iodine in milk affects the risk of iodine deficiency or excess in the population., Objective: The first goal of this study was to develop a model to predict the iodine concentration in milk based on the concentration of iodine and rapeseed or glucosinolate in feed, as a tool to securing stable iodine concentration in milk. A second aim was to estimate the impact of different iodine levels in milk on iodine nutrition in the Norwegian population., Design: Two models were developed on the basis of results from eight published and two unpublished studies from the past 20 years. The models were based on different iodine concentrations in the fodder combined with either glucosinolate (Model 1) or rapeseed cake/meal (Model 2). To illustrate the impact of different iodine concentrations in milk on iodine intake, we simulated the iodine contribution from dairy products in different population groups based on food intake data in the most recent dietary surveys in Norway., Results: The models developed could predict iodine concentration in milk. Cross-validation showed good fit and confirmed the explanatory power of the models. Our calculations showed that dairy products with current iodine level in milk (200 µg/kg) cover 68, 49, 108 and 56% of the daily iodine requirements for men, women, 2-year-old children, and pregnant women, respectively., Conclusions: Securing a stable level of iodine in milk by adjusting iodine concentration in different cow feeds is thus important for preventing excess intake in small children and iodine deficiency in pregnant and non-pregnant women.

Dynamic contrast enhanced MRI (DCE-MRI) provides insight into the vascular properties of tissue. Pharmacokinetic models may be fitted to DCE-MRI uptake patterns, enabling biologically relevant interpretations. The aim of our study was to determine whether treatment outcome for 81 patients with locally advanced cervical cancer could be predicted from parameters of the Brix pharmacokinetic model derived from pre-chemoradiotherapy DCE-MRI. First-order statistical features of the Brix parameters were used. In addition, texture analysis of Brix parameter maps was done by constructing gray level co-occurrence matrices (GLCM) from the maps. Clinical factors and first- and second-order features were used as explanatory variables for support vector machine (SVM) classification, with treatment outcome as response. Classification models were validated using leave-one-out cross-model validation. A random value permutation test was used to evaluate model significance. Features derived from first-order statistics could not discriminate between cured and relapsed patients (specificity 0%-20%, p-values close to unity). However, second-order GLCM features could significantly predict treatment outcome with accuracies (~70%) similar to the clinical factors tumor volume and stage (69%). The results indicate that the spatial relations within the tumor, quantified by texture features, were more suitable for outcome prediction than first-order features.

Purpose: Idiopathic intracranial hypertension (IIH) is a condition of increased intracranial pressure of unknown aetiology. Patients with IIH usually suffer from headache and visual disturbances. High intracranial pressure despite normal ventricle size and negative MRI indicate perturbed water flux across cellular membranes, which is provided by the brain water channel aquaporin-4 (AQP4). IIH could be associated with malfunctioning intracerebral water homeostasis and cerebrospinal fluid (CSF) reabsorption based on functional or regulatory alterations of AQP4., Methods: Clinical data, blood and CSF samples were collected from 28 patients with IIH. Clinical characteristics were assessed, and a genetic association study was performed by sequencing the AQP4 gene on chromosome 18. Genetic data were compared with 52 healthy controls and matched by age, sex and ethnicity. Chi-square test and linear discriminant analysis (LDA) were used in the search of a genotype-phenotype association., Results: While the majority of patients responded to medical treatment, four required shunt application. All, except one, had a good visual outcome. The 24 AQP4 gene SNPs showed no association with IIH. Full cross-validation of the LDA modelling resulted in only 55.1% correct classification of the cases and controls, with a corresponding estimated p-value 0.37., Conclusions: Our genetic case-control study did not indicate an association between AQP4 gene variants and IIH. However, the theory of an etiopathogenic link between IIH and AQP4 is tempting, and discussed in this article. Association studies with large sample size are difficult to perform owing is the rarity of the condition., (© 2011 The Authors. Acta Ophthalmologica © 2011 Acta Ophthalmologica Scandinavica Foundation.)

Background: Statistical approaches to describing the behaviour, including the complex relationships between input parameters and model outputs, of nonlinear dynamic models (referred to as metamodelling) are gaining more and more acceptance as a means for sensitivity analysis and to reduce computational demand. Understanding such input-output maps is necessary for efficient model construction and validation. Multi-way metamodelling provides the opportunity to retain the block-wise structure of the temporal data typically generated by dynamic models throughout the analysis. Furthermore, a cluster-based approach to regional metamodelling allows description of highly nonlinear input-output relationships, revealing additional patterns of covariation., Results: By presenting the N-way Hierarchical Cluster-based Partial Least Squares Regression (N-way HC-PLSR) method, we here combine multi-way analysis with regional cluster-based metamodelling, together making a powerful methodology for extensive exploration of the input-output maps of complex dynamic models. We illustrate the potential of the N-way HC-PLSR by applying it both to predict model outputs as functions of the input parameters, and in the inverse direction (predicting input parameters from the model outputs), to analyse the behaviour of a dynamic model of the mammalian circadian clock. Our results display a more complete cartography of how variation in input parameters is reflected in the temporal behaviour of multiple model outputs than has been previously reported., Conclusions: Our results indicated that the N-way HC-PLSR metamodelling provides a gain in insight into which parameters that are related to a specific model output behaviour, as well as variations in the model sensitivity to certain input parameters across the model output space. Moreover, the N-way approach allows a more transparent and detailed exploration of the temporal dimension of complex dynamic models, compared to alternative 2-way methods.

Background: Deterministic dynamic models of complex biological systems contain a large number of parameters and state variables, related through nonlinear differential equations with various types of feedback. A metamodel of such a dynamic model is a statistical approximation model that maps variation in parameters and initial conditions (inputs) to variation in features of the trajectories of the state variables (outputs) throughout the entire biologically relevant input space. A sufficiently accurate mapping can be exploited both instrumentally and epistemically. Multivariate regression methodology is a commonly used approach for emulating dynamic models. However, when the input-output relations are highly nonlinear or non-monotone, a standard linear regression approach is prone to give suboptimal results. We therefore hypothesised that a more accurate mapping can be obtained by locally linear or locally polynomial regression. We present here a new method for local regression modelling, Hierarchical Cluster-based PLS regression (HC-PLSR), where fuzzy C-means clustering is used to separate the data set into parts according to the structure of the response surface. We compare the metamodelling performance of HC-PLSR with polynomial partial least squares regression (PLSR) and ordinary least squares (OLS) regression on various systems: six different gene regulatory network models with various types of feedback, a deterministic mathematical model of the mammalian circadian clock and a model of the mouse ventricular myocyte function., Results: Our results indicate that multivariate regression is well suited for emulating dynamic models in systems biology. The hierarchical approach turned out to be superior to both polynomial PLSR and OLS regression in all three test cases. The advantage, in terms of explained variance and prediction accuracy, was largest in systems with highly nonlinear functional relationships and in systems with positive feedback loops., Conclusions: HC-PLSR is a promising approach for metamodelling in systems biology, especially for highly nonlinear or non-monotone parameter to phenotype maps. The algorithm can be flexibly adjusted to suit the complexity of the dynamic model behaviour, inviting automation in the metamodelling of complex systems.

A new method is presented for extraction of population firing-rate models for both thalamocortical and intracortical signal transfer based on stimulus-evoked data from simultaneous thalamic single-electrode and cortical recordings using linear (laminar) multielectrodes in the rat barrel system. Time-dependent population firing rates for granular (layer 4), supragranular (layer 2/3), and infragranular (layer 5) populations in a barrel column and the thalamic population in the homologous barreloid are extracted from the high-frequency portion (multi-unit activity; MUA) of the recorded extracellular signals. These extracted firing rates are in turn used to identify population firing-rate models formulated as integral equations with exponentially decaying coupling kernels, allowing for straightforward transformation to the more common firing-rate formulation in terms of differential equations. Optimal model structures and model parameters are identified by minimizing the deviation between model firing rates and the experimentally extracted population firing rates. For the thalamocortical transfer, the experimental data favor a model with fast feedforward excitation from thalamus to the layer-4 laminar population combined with a slower inhibitory process due to feedforward and/or recurrent connections and mixed linear-parabolic activation functions. The extracted firing rates of the various cortical laminar populations are found to exhibit strong temporal correlations for the present experimental paradigm, and simple feedforward population firing-rate models combined with linear or mixed linear-parabolic activation function are found to provide excellent fits to the data. The identified thalamocortical and intracortical network models are thus found to be qualitatively very different. While the thalamocortical circuit is optimally stimulated by rapid changes in the thalamic firing rate, the intracortical circuits are low-pass and respond most strongly to slowly varying inputs from the cortical layer-4 population.

A novel approach for revealing patterns of proteome variation among series of 2-DE gel images is presented. The approach utilises image alignment to ensure that each pixel represents the same information across all gels. Gel images are normalised, and background corrected, followed by unfolding of the images to 1-D pixel vectors and analysing pixel vectors by multivariate data modelling. Information resulting from the data analysis is refolded back to the image domain for visualisation and interpretation. The method is rapid and suitable for automatic routines applied after the gel alignment. The approach is compared with spot volume analysis to illustrate how this approach can solve persistent problems like mismatch of protein spots, erroneous missing values and failure to detect variation in overlapping proteins. The method may also detect variation in the border area of saturated proteins. The approach is given the name pixel-based analysis of multiple images for the identification of changes (PMC). The method can be used for multiple images in general. Effects of pretreatment of the images are discussed.

The present work investigates the possibility of constructing a multivariate calibration model for predicting the composition of ground beef with respect to different meat quality types, based on intensity profiles from isoelectric focusing of water-soluble proteins. Beef mixtures containing various amounts of mechanically recovered meat, head meat and production meat from beef, were analysed by isoelectric focusing in immobilised pH-gradients. The gels were photographed and the images transferred to a digital format. By simple image processing procedures, background colour was virtually eliminated and signal strength was improved to a considerable degree. Multivariate analysis of protein profiles from the gels gave models explaining 75 to 90% of variance in sample composition. Manually deboned meat was explained to the highest degree, and with a precision of 7%. Two different qualities of mechanically recovered meat could be detected even when treated as one category. The present approach needs further refinement, but seems applicable for detecting intentional substitution of high quality meat products with low-price raw materials. One advantage of the approach is that evaluation of samples is not dependent on specific knowledge on the individual components to be analysed, so that such analytical methods are relatively easy to implement in any standard laboratory.