Multicentre study for a robust protocol in single-voxel spectroscopy: quantification of MRS signals by time-domain fitting algorithms

Magnetic Resonance Spectroscopy (MRS) is an advanced clinical and research application which guarantees a specific biochemical and metabolic characterization of tissues by the detection and quantification of key metabolites for diagnosis and disease staging. The "Associazione Italiana di Fisica Medica (AIFM)" has promoted the activity of the "Interconfronto di spettroscopia in RM" working group. The purpose of the study is to compare and analyze results obtained by perfoming MRS on scanners of different manufacturing in order to compile a robust protocol for spectroscopic examinations in clinical routines. This thesis takes part into this project by using the GE Signa HDxt 1.5 T at the Pavillion no. 11 of the S.Orsola-Malpighi hospital in Bologna. The spectral analyses have been performed with the jMRUI package, which includes a wide range of preprocessing and quantification algorithms for signal analysis in the time domain. After the quality assurance on the scanner with standard and innovative methods, both spectra with and without suppression of the water peak have been acquired on the GE test phantom. The comparison of the ratios of the metabolite amplitudes over Creatine computed by the workstation software, which works on the frequencies, and jMRUI shows good agreement, suggesting that quantifications in both domains may lead to consistent results. The characterization of an in-house phantom provided by the working group has achieved its goal of assessing the solution content and the metabolite concentrations with good accuracy. The goodness of the experimental procedure and data analysis has been demonstrated by the correct estimation of the T2 of water, the observed biexponential relaxation curve of Creatine and the correct TE value at which the modulation by J coupling causes the Lactate doublet to be inverted in the spectrum. The work of this thesis has demonstrated that it is possible to perform measurements and establish protocols for data analysis, based on the physical principles of NMR, which are able to provide robust values for the spectral parameters of clinical use.

A Robust Parser of Czech

Mr. Kubon's project was inspired by the growing need for an automatic, syntactic analyser (parser) of Czech, which could be used in the syntactic processing of large amounts of texts. Mr. Kubon notes that such a tool would be very useful, especially in the field of corpus linguistics, where creating a large-scale "tree bank" (a collection of syntactic representations of natural language sentences) is a very important step towards the investigation of the properties of a given language. The work involved in syntactically parsing a whole corpus in order to get a representative set of syntactic structures would be almost inconceivable without the help of some kind of robust (semi)automatic parser. The need for the automatic natural language parser to be robust increases with the size of the linguistic data in the corpus or in any other kind of text which is going to be parsed. Practical experience shows that apart from syntactically correct sentences, there are many sentences which contain a "real" grammatical error. These sentences may be corrected in small-scale texts, but not generally in the whole corpus. In order to be able to complete the overall project, it was necessary to address a number of smaller problems. These were; 1. the adaptation of a suitable formalism able to describe the formal grammar of the system; 2. the definition of the structure of the system's dictionary containing all relevant lexico-syntactic information, and the development of a formal grammar able to robustly parse Czech sentences from the test suite; 3. filling the syntactic dictionary with sample data allowing the system to be tested and debugged during its development (about 1000 words); 4. the development of a set of sample sentences containing a reasonable amount of grammatical and ungrammatical phenomena covering some of the most typical syntactic constructions being used in Czech. Number 3, building a formal grammar, was the main task of the project. The grammar is of course far from complete (Mr. Kubon notes that it is debatable whether any formal grammar describing a natural language may ever be complete), but it covers the most frequent syntactic phenomena, allowing for the representation of a syntactic structure of simple clauses and also the structure of certain types of complex sentences. The stress was not so much on building a wide coverage grammar, but on the description and demonstration of a method. This method uses a similar approach as that of grammar-based grammar checking. The problem of reconstructing the "correct" form of the syntactic representation of a sentence is closely related to the problem of localisation and identification of syntactic errors. Without a precise knowledge of the nature and location of syntactic errors it is not possible to build a reliable estimation of a "correct" syntactic tree. The incremental way of building the grammar used in this project is also an important methodological issue. Experience from previous projects showed that building a grammar by creating a huge block of metarules is more complicated than the incremental method, which begins with the metarules covering most common syntactic phenomena first, and adds less important ones later, especially from the point of view of testing and debugging the grammar. The sample of the syntactic dictionary containing lexico-syntactical information (task 4) now has slightly more than 1000 lexical items representing all classes of words. During the creation of the dictionary it turned out that the task of assigning complete and correct lexico-syntactic information to verbs is a very complicated and time-consuming process which would itself be worth a separate project. The final task undertaken in this project was the development of a method allowing effective testing and debugging of the grammar during the process of its development. The problem of the consistency of new and modified rules of the formal grammar with the rules already existing is one of the crucial problems of every project aiming at the development of a large-scale formal grammar of a natural language. This method allows for the detection of any discrepancy or inconsistency of the grammar with respect to a test-bed of sentences containing all syntactic phenomena covered by the grammar. This is not only the first robust parser of Czech, but also one of the first robust parsers of a Slavic language. Since Slavic languages display a wide range of common features, it is reasonable to claim that this system may serve as a pattern for similar systems in other languages. To transfer the system into any other language it is only necessary to revise the grammar and to change the data contained in the dictionary (but not necessarily the structure of primary lexico-syntactic information). The formalism and methods used in this project can be used in other Slavic languages without substantial changes.

Robust Inferences For Covariate Effects On Survival Time With Censored Linear Regression Models

Various inference procedures for linear regression models with censored failure times have been studied extensively. Recent developments on efficient algorithms to implement these procedures enhance the practical usage of such models in survival analysis. In this article, we present robust inferences for certain covariate effects on the failure time in the presence of "nuisance" confounders under a semiparametric, partial linear regression setting. Specifically, the estimation procedures for the regression coefficients of interest are derived from a working linear model and are valid even when the function of the confounders in the model is not correctly specified. The new proposals are illustrated with two examples and their validity for cases with practical sample sizes is demonstrated via a simulation study.

USING THE R PACKAGE crlmm FOR GENOTYPING AND COPY NUMBER ESTIMATION

Genotyping platforms such as Affymetrix can be used to assess genotype-phenotype as well as copy number-phenotype associations at millions of markers. While genotyping algorithms are largely concordant when assessed on HapMap samples, tools to assess copy number changes are more variable and often discordant. One explanation for the discordance is that copy number estimates are susceptible to systematic differences between groups of samples that were processed at different times or by different labs. Analysis algorithms that do not adjust for batch effects are prone to spurious measures of association. The R package crlmm implements a multilevel model that adjusts for batch effects and provides allele-specific estimates of copy number. This paper illustrates a workflow for the estimation of allele-specific copy number, develops markerand study-level summaries of batch effects, and demonstrates how the marker-level estimates can be integrated with complimentary Bioconductor software for inferring regions of copy number gain or loss. All analyses are performed in the statistical environment R. A compendium for reproducing the analysis is available from the author’s website (http://www.biostat.jhsph.edu/~rscharpf/crlmmCompendium/index.html).

Accurate and robust reconstruction of proximal femur from sparse intraoperative data and dense point distribution model for surgical navigation

Constructing a 3D surface model from sparse-point data is a nontrivial task. Here, we report an accurate and robust approach for reconstructing a surface model of the proximal femur from sparse-point data and a dense-point distribution model (DPDM). The problem is formulated as a three-stage optimal estimation process. The first stage, affine registration, is to iteratively estimate a scale and a rigid transformation between the mean surface model of the DPDM and the sparse input points. The estimation results of the first stage are used to establish point correspondences for the second stage, statistical instantiation, which stably instantiates a surface model from the DPDM using a statistical approach. This surface model is then fed to the third stage, kernel-based deformation, which further refines the surface model. Handling outliers is achieved by consistently employing the least trimmed squares (LTS) approach with a roughly estimated outlier rate in all three stages. If an optimal value of the outlier rate is preferred, we propose a hypothesis testing procedure to automatically estimate it. We present here our validations using four experiments, which include 1 leave-one-out experiment, 2 experiment on evaluating the present approach for handling pathology, 3 experiment on evaluating the present approach for handling outliers, and 4 experiment on reconstructing surface models of seven dry cadaver femurs using clinically relevant data without noise and with noise added. Our validation results demonstrate the robust performance of the present approach in handling outliers, pathology, and noise. An average 95-percentile error of 1.7-2.3 mm was found when the present approach was used to reconstruct surface models of the cadaver femurs from sparse-point data with noise added.

Unifying energy minimization and mutual information maximization for robust 2D/3D registration of X-ray and CT images

Similarity measure is one of the main factors that affect the accuracy of intensity-based 2D/3D registration of X-ray fluoroscopy to CT images. Information theory has been used to derive similarity measure for image registration leading to the introduction of mutual information, an accurate similarity measure for multi-modal and mono-modal image registration tasks. However, it is known that the standard mutual information measure only takes intensity values into account without considering spatial information and its robustness is questionable. Previous attempt to incorporate spatial information into mutual information either requires computing the entropy of higher dimensional probability distributions, or is not robust to outliers. In this paper, we show how to incorporate spatial information into mutual information without suffering from these problems. Using a variational approximation derived from the Kullback-Leibler bound, spatial information can be effectively incorporated into mutual information via energy minimization. The resulting similarity measure has a least-squares form and can be effectively minimized by a multi-resolution Levenberg-Marquardt optimizer. Experimental results are presented on datasets of two applications: (a) intra-operative patient pose estimation from a few (e.g. 2) calibrated fluoroscopic images, and (b) post-operative cup alignment estimation from single X-ray radiograph with gonadal shielding.

Long-distance photogrammetric trait estimation in free-ranging animals: A new approach

The acquisition of accurate information on the size of traits in animals is fundamental for the study of animal ecology and evolution and their management. We demonstrate how morphological traits of free-ranging animals can reliably be estimated on very large observation distances of several hundred meters by the use of ordinary digital photographic equipment and simple photogrammetric software. In our study, we estimated the length of horn annuli in free-ranging male Alpine ibex (Capra ibex) by taking already measured horn annuli of conspecifics on the same photographs as scaling units. Comparisons with hand-measured horn annuli lengths and repeatability analyses revealed a high accuracy of the photogrammetric estimates. If length estimations of specific horn annuli are based on multiple photographs measurement errors of <5.5 mm can be expected. In the current study the application of the described photogrammetric procedure increased the sample size of animals with known horn annuli length by an additional 104%. The presented photogrammetric procedure is of broad applicability and represents an easy, robust and cost-efficient method for the measuring of individuals in populations where animals are hard to capture or to approach.

Automatic X-ray landmark detection and shape segmentation via data-driven joint estimation of image displacements

In this paper, we propose a new method for fully-automatic landmark detection and shape segmentation in X-ray images. To detect landmarks, we estimate the displacements from some randomly sampled image patches to the (unknown) landmark positions, and then we integrate these predictions via a voting scheme. Our key contribution is a new algorithm for estimating these displacements. Different from other methods where each image patch independently predicts its displacement, we jointly estimate the displacements from all patches together in a data driven way, by considering not only the training data but also geometric constraints on the test image. The displacements estimation is formulated as a convex optimization problem that can be solved efficiently. Finally, we use the sparse shape composition model as the a priori information to regularize the landmark positions and thus generate the segmented shape contour. We validate our method on X-ray image datasets of three different anatomical structures: complete femur, proximal femur and pelvis. Experiments show that our method is accurate and robust in landmark detection, and, combined with the shape model, gives a better or comparable performance in shape segmentation compared to state-of-the art methods. Finally, a preliminary study using CT data shows the extensibility of our method to 3D data.

Stereological estimation of particle shape and orientation from volume tensors

In the present paper, we describe new robust methods of estimating cell shape and orientation in 3D from sections. The descriptors of 3D cell shape and orientation are based on volume tensors which are used to construct an ellipsoid, the Miles ellipsoid, approximating the average cell shape and orientation in 3D. The estimators of volume tensors are based on observations in several optical planes through sampled cells. This type of geometric sampling design is known as the optical rotator. The statistical behaviour of the estimator of the Miles ellipsoid is studied under a flexible model for 3D cell shape and orientation. In a simulation study, the lengths of the axes of the Miles ellipsoid can be estimated with CVs of about 2% if 100 cells are sampled. Finally, we illustrate the use of the developed methods in an example, involving neurons in the medial prefrontal cortex of rat.

Outcome-based adaptive randomization for binary data in clinical trials---Compare and contrast

Monte Carlo simulation has been conducted to investigate parameter estimation and hypothesis testing in some well known adaptive randomization procedures. The four urn models studied are Randomized Play-the-Winner (RPW), Randomized Pôlya Urn (RPU), Birth and Death Urn with Immigration (BDUI), and Drop-the-Loses Urn (DL). Two sequential estimation methods, the sequential maximum likelihood estimation (SMLE) and the doubly adaptive biased coin design (DABC), are simulated at three optimal allocation targets that minimize the expected number of failures under the assumption of constant variance of simple difference (RSIHR), relative risk (ORR), and odds ratio (OOR) respectively. Log likelihood ratio test and three Wald-type tests (simple difference, log of relative risk, log of odds ratio) are compared in different adaptive procedures. ^ Simulation results indicates that although RPW is slightly better in assigning more patients to the superior treatment, the DL method is considerably less variable and the test statistics have better normality. When compared with SMLE, DABC has slightly higher overall response rate with lower variance, but has larger bias and variance in parameter estimation. Additionally, the test statistics in SMLE have better normality and lower type I error rate, and the power of hypothesis testing is more comparable with the equal randomization. Usually, RSIHR has the highest power among the 3 optimal allocation ratios. However, the ORR allocation has better power and lower type I error rate when the log of relative risk is the test statistics. The number of expected failures in ORR is smaller than RSIHR. It is also shown that the simple difference of response rates has the worst normality among all 4 test statistics. The power of hypothesis test is always inflated when simple difference is used. On the other hand, the normality of the log likelihood ratio test statistics is robust against the change of adaptive randomization procedures. ^

HPV vaccine coverage in Texas counties: An application of multilevel, small area estimation

Health departments, research institutions, policy-makers, and healthcare providers are often interested in knowing the health status of their clients/constituents. Without the resources, financially or administratively, to go out into the community and conduct health assessments directly, these entities frequently rely on data from population-based surveys to supply the information they need. Unfortunately, these surveys are ill-equipped for the job due to sample size and privacy concerns. Small area estimation (SAE) techniques have excellent potential in such circumstances, but have been underutilized in public health due to lack of awareness and confidence in applying its methods. The goal of this research is to make model-based SAE accessible to a broad readership using clear, example-based learning. Specifically, we applied the principles of multilevel, unit-level SAE to describe the geographic distribution of HPV vaccine coverage among females aged 11-26 in Texas.^ Multilevel (3 level: individual, county, public health region) random-intercept logit models of HPV vaccination (receipt of ≥ 1 dose Gardasil® ) were fit to data from the 2008 Behavioral Risk Factor Surveillance System (outcome and level 1 covariates) and a number of secondary sources (group-level covariates). Sampling weights were scaled (level 1) or constructed (levels 2 & 3), and incorporated at every level. Using the regression coefficients (and standard errors) from the final models, I simulated 10,000 datasets for each regression coefficient from the normal distribution and applied them to the logit model to estimate HPV vaccine coverage in each county and respective demographic subgroup. For simplicity, I only provide coverage estimates (and 95% confidence intervals) for counties.^ County-level coverage among females aged 11-17 varied from 6.8-29.0%. For females aged 18-26, coverage varied from 1.9%-23.8%. Aggregated to the state level, these values translate to indirect state estimates of 15.5% and 11.4%, respectively; both of which fall within the confidence intervals for the direct estimates of HPV vaccine coverage in Texas (Females 11-17: 17.7%, 95% CI: 13.6, 21.9; Females 18-26: 12.0%, 95% CI: 6.2, 17.7).^ Small area estimation has great potential for informing policy, program development and evaluation, and the provision of health services. Harnessing the flexibility of multilevel, unit-level SAE to estimate HPV vaccine coverage among females aged 11-26 in Texas counties, I have provided (1) practical guidance on how to conceptualize and conduct modelbased SAE, (2) a robust framework that can be applied to other health outcomes or geographic levels of aggregation, and (3) HPV vaccine coverage data that may inform the development of health education programs, the provision of health services, the planning of additional research studies, and the creation of local health policies.^

Bayesian estimation of multilevel item response model with missing data

This study proposed a novel statistical method that modeled the multiple outcomes and missing data process jointly using item response theory. This method follows the "intent-to-treat" principle in clinical trials and accounts for the correlation between outcomes and missing data process. This method may provide a good solution to chronic mental disorder study. ^ The simulation study demonstrated that if the true model is the proposed model with moderate or strong correlation, ignoring the within correlation may lead to overestimate of the treatment effect and result in more type I error than specified level. Even if the within correlation is small, the performance of proposed model is as good as naïve response model. Thus, the proposed model is robust for different correlation settings if the data is generated by the proposed model.^

DEVELOPMENT OF A BEAM-SPECIFIC PLANNING TARGET VOLUME AND A ROBUST PLAN ANALYSIS TOOL FOR PROTON THERAPY

Proton therapy is growing increasingly popular due to its superior dose characteristics compared to conventional photon therapy. Protons travel a finite range in the patient body and stop, thereby delivering no dose beyond their range. However, because the range of a proton beam is heavily dependent on the tissue density along its beam path, uncertainties in patient setup position and inherent range calculation can degrade thedose distribution significantly. Despite these challenges that are unique to proton therapy, current management of the uncertainties during treatment planning of proton therapy has been similar to that of conventional photon therapy. The goal of this dissertation research was to develop a treatment planning method and a planevaluation method that address proton-specific issues regarding setup and range uncertainties. Treatment plan designing method adapted to proton therapy: Currently, for proton therapy using a scanning beam delivery system, setup uncertainties are largely accounted for by geometrically expanding a clinical target volume (CTV) to a planning target volume (PTV). However, a PTV alone cannot adequately account for range uncertainties coupled to misaligned patient anatomy in the beam path since it does not account for the change in tissue density. In order to remedy this problem, we proposed a beam-specific PTV (bsPTV) that accounts for the change in tissue density along the beam path due to the uncertainties. Our proposed method was successfully implemented, and its superiority over the conventional PTV was shown through a controlled experiment.. Furthermore, we have shown that the bsPTV concept can be incorporated into beam angle optimization for better target coverage and normal tissue sparing for a selected lung cancer patient. Treatment plan evaluation method adapted to proton therapy: The dose-volume histogram of the clinical target volume (CTV) or any other volumes of interest at the time of planning does not represent the most probable dosimetric outcome of a given plan as it does not include the uncertainties mentioned earlier. Currently, the PTV is used as a surrogate of the CTV’s worst case scenario for target dose estimation. However, because proton dose distributions are subject to change under these uncertainties, the validity of the PTV analysis method is questionable. In order to remedy this problem, we proposed the use of statistical parameters to quantify uncertainties on both the dose-volume histogram and dose distribution directly. The robust plan analysis tool was successfully implemented to compute both the expectation value and its standard deviation of dosimetric parameters of a treatment plan under the uncertainties. For 15 lung cancer patients, the proposed method was used to quantify the dosimetric difference between the nominal situation and its expected value under the uncertainties.

Grapevine Yield and Leaf Area Estimation Using Supervised Classification Methodology on RGB Images Taken under Field Conditions

The aim of this research was to implement a methodology through the generation of a supervised classifier based on the Mahalanobis distance to characterize the grapevine canopy and assess leaf area and yield using RGB images. The method automatically processes sets of images, and calculates the areas (number of pixels) corresponding to seven different classes (Grapes, Wood, Background, and four classes of Leaf, of increasing leaf age). Each one is initialized by the user, who selects a set of representative pixels for every class in order to induce the clustering around them. The proposed methodology was evaluated with 70 grapevine (V. vinifera L. cv. Tempranillo) images, acquired in a commercial vineyard located in La Rioja (Spain), after several defoliation and de-fruiting events on 10 vines, with a conventional RGB camera and no artificial illumination. The segmentation results showed a performance of 92% for leaves and 98% for clusters, and allowed to assess the grapevine’s leaf area and yield with R2 values of 0.81 (p < 0.001) and 0.73 (p = 0.002), respectively. This methodology, which operates with a simple image acquisition setup and guarantees the right number and kind of pixel classes, has shown to be suitable and robust enough to provide valuable information for vineyard management.

Estimation of daily global solar radiation from measured temperatures at Cañada de Luque, Córdoba, Argentina

Solar radiation is the most important source of renewable energy in the planet; it's important to solar engineers, designers and architects, and it's also fundamental for efficiently determining irrigation water needs and potential yield of crops, among others. Complete and accurate solar radiation data at a specific region are indispensable. For locations where measured values are not available, several models have been developed to estimate solar radiation. The objective of this paper was to calibrate, validate and compare five representative models to predict global solar radiation, adjusting the empirical coefficients to increase the local applicability and to develop a linear model. All models were based on easily available meteorological variables, without sunshine hours as input, and were used to estimate the daily solar radiation at Cañada de Luque (Córdoba, Argentina). As validation, measured and estimated solar radiation data were analyzed using several statistic coefficients. The results showed that all the analyzed models were robust and accurate (R2 and RMSE values between 0.87 to 0.89 and 2.05 to 2.14, respectively), so global radiation can be estimated properly with easily available meteorological variables when only temperature data are available. Hargreaves-Samani, Allen and Bristow-Campbell models could be used with typical values to estimate solar radiation while Samani and Almorox models should be applied with calibrated coefficients. Although a new linear model presented the smallest R2 value (R2 = 0.87), it could be considered useful for its easy application. The daily global solar radiation values produced for these models can be used to estimate missing daily values, when only temperature data are available, and in hydrologic or agricultural applications.