| 1. |
- Amiri, Saeid, 1976-
(författare)
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On the Application of the Bootstrap : Coefficient of Variation, Contingency Table, Information Theory and Ranked Set Sampling
- 2011
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- This thesis deals with the bootstrap method. Three decades after the seminal paper by Bradly Efron, still the horizons of this method need more exploration. The research presented herein has stepped into different fields of statistics where the bootstrap method can be utilized as a fundamental statistical tool in almost any application. The thesis considers various statistical problems, which is explained briefly below. Bootstrap method: A comparison of the parametric and the nonparametric bootstrap of variance is presented. The bootstrap of ranked set sampling is dealt with, as well as the wealth of theories and applications on the RSS bootstrap that exist nowadays. Moreover, the performance of RSS in resampling is explored. Furthermore, the application of the bootstrap method in the inference of contingency table test is studied. Coefficient of variation: This part shows the capacity of the bootstrap for inferring the coefficient of variation, a task which the asymptotic method does not perform very well. Information theory: There are few works on the study of information theory, especially on the inference of entropy. The papers included in this thesis try to achieve the inference of entropy using the bootstrap method.
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| 2. |
- Berndtsson, Rolf, 1936-
(författare)
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Om folkhögskolans dynamik : Möten mellan olika bildningsprojekt
- 2000
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- This study is describing the projects of Bildung which are possible to identify with the students and the teachers at two folk high schools and the meeting between those projects in the classrooms. Another purpose is to describe and analyze processes, which arise when teachers, students and folk high school as an institution come together. As a background and part of the study, connected to the central concept of the thesis - power and Bildung - is an account of the projects of Bildung which have been developed within the folk high school in a historical perspective. It is the generally oriented course and the students that are in focus.The study is part of an ethnographic research tradition and the empirical part of the study consists of a combination of qualitative interviews with the teachers and the students and participant observation.The projects of Bildung, which I have found represented by the students are “selfeducation” with the subgroups "self-development" and "self-rehabilitation" and "the project of qualification". Most of the teachers try to establish an attitude that has a self-educational direction but gradually the teachers are forced to let the qualification project get a more prominent part in the teaching. The projects of Bildung are changing and are in contrast to each other, sometimes in harmony and sometimes out of balance. I found that the study setting could be characterized by manifoldness and dynamics. A pluralism resulting in challenges and different processes.
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| 3. |
- Bornefalk Hermansson, Anna, 1971-
(författare)
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Resampling Evaluation of Signal Detection and Classification : With Special Reference to Breast Cancer, Computer-Aided Detection and the Free-Response Approach
- 2007
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The first part of this thesis is concerned with trend modelling of breast cancer mortality rates. By using an age-period-cohort model, the relative contributions of period and cohort effects are evaluated once the unquestionable existence of the age effect is controlled for. The result of such a modelling gives indications in the search for explanatory factors. While this type of modelling is usually performed with 5-year period intervals, the use of 1-year period data, as in Paper I, may be more appropriate.The main theme of the thesis is the evaluation of the ability to detect signals in x-ray images of breasts. Early detection is the most important tool to achieve a reduction in breast cancer mortality rates, and computer-aided detection systems can be an aid for the radiologist in the diagnosing process.The evaluation of computer-aided detection systems includes the estimation of distributions. One way of obtaining estimates of distributions when no assumptions are at hand is kernel density estimation, or the adaptive version thereof that smoothes to a greater extent in the tails of the distribution, thereby reducing spurious effects caused by outliers. The technique is described in the context of econometrics in Paper II and then applied together with the bootstrap in the breast cancer research area in Papers III-V.Here, estimates of the sampling distributions of different parameters are used in a new model for free-response receiver operating characteristic (FROC) curve analysis. Compared to earlier work in the field, this model benefits from the advantage of not assuming independence of detections in the images, and in particular, from the incorporation of the sampling distribution of the system's operating point.Confidence intervals obtained from the proposed model with different approaches with respect to the estimation of the distributions and the confidence interval extraction methods are compared in terms of coverage and length of the intervals by simulations of lifelike data.
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| 4. |
- Christensen, Kjeld, 1957-
(författare)
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Platelet Activation and Inhibition in Connection with Vascular Stents
- 2007
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- This thesis describes the Chandler loop, which makes it possible to conduct studies in vitro of molecular and cellular interactions between whole blood and stents. It was possible to monitor activation and inhibition of the cascades systems, leukocytes and platelets by combining different platelet inhibitors and heparin coating of stents. The clinical study was performed on patients with ACS undergoing PCI and stent implantation. In this study platelet activation markers P-selectin, and αIIb/β3 as well as inflammatory markers were followed from baseline during the first 48 hours post-PCI. The same parameters were evaluated in healthy controls for comparison at baseline. In vitro: The activation of blood in the Chandler loops were more pronounced for unmodified stent grafts than for partially heparin coated stent grafts. Heparin coated stent grafts dreated the same activation as the loops alone. This indicated that the Chandler loop system was a feasible tool for evaluation of blood compability of stents. Heparin coating of stents significantly reduced TAT, CD11b and platelet activation. The combination of a heparin coated stent and abciximab reduced TAT and contact activation, as compared to abciximab or heparin coating alone. Heparin coating of stents in combination with AR-C69931MX resulted in a significant reduction in TAT and preservation of the platelet count but had no effect on contact activation. Clinical study: Abciximab resulted in an almost total inhibition of fibrinogen binding to platelets and persisted throughout the observation period. Clopidogrel effectscould be observed at four hours but was more pronounced at 24 hours. P-selectin expression did not differ over time between groups, indicating that platelet activation with α-granule secretion was not affected by abciximab treatment. The hs-CRP, C3a and sC5b-9 levels increased 24 to 48 hours after PCI in patients with ACS. FXIIa-C1inh was reduced in ACS patients receiving abciximab as compared to controls. The elevated bFGF levels at baseline returned to the levels observed in controls four hours after PCI and stent implantation, whereas an increase in VEGF was observed 24 hours post-PCI.
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| 5. |
- Ekström, Joakim, 1982-
(författare)
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Contributions to the Theory of Measures of Association for Ordinal Variables
- 2009
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- In this thesis, we consider measures of association for ordinal variables from a theoretical perspective. In particular, we study the phi-coefficient, the tetrachoric correlation coefficient and the polychoric correlation coefficient. We also introduce a new measure of association for ordinal variables, the empirical polychoric correlation coefficient, which has better theoretical properties than the polychoric correlation coefficient, including greatly enhanced robustness. In the first article, entitled ``On the relation between the phi-coefficient and the tetrachoric correlation coefficient'', we show that under given marginal probabilities there exists a continuous bijection between the two measures of association. Furthermore, we show that the bijection has a fixed point at zero for all marginal probabilities. Consequently, the choice of which of these measures of association to use is for all practical purposes a matter of preference only. In the second article, entitled ``A generalized definition of the tetrachoric correlation coefficient'', we generalize the tetrachoric correlation coefficient so that a large class of parametric families of bivariate distributions can be assumed as underlying distributions. We also provide a necessary and sufficient condition for the generalized tetrachoric correlation coefficient to be well defined for a given parametric family of bivariate distributions. With examples, we illustrate the effects on the polychoric correlation coefficient of different distributional assumptions. In the third article, entitled ``A generalized definition of the polychoric correlation coefficient'', we generalize the polychoric correlation coefficient to a large class of parametric families of bivariate distributions, and show that the generalized and the conventional polychoric correlation coefficients agree on the family of bivariate normal distributions. With examples, we illustrate the effects of different distributional assumptions on the polychoric correlation coefficient. In combination with goodness-of-fit p-values, the association analysis can be enriched with a consideration of possible tail dependence. In the fourth article, we propose a new measure of association for ordinal variables, named the empirical polychoric correlation coefficient. The empirical polychoric correlation coefficient relaxes the fundamental assumption of the polychoric correlation coefficient so that an underlying joint distribution is only assumed to exist, not to be of a particular parametric family. We also provide an asymptotical result, by which the empirical polychoric correlation coefficient converges almost surely to the true polychoric correlation under very general conditions. Thus, the proposed empirical polychoric correlation coefficient has better theoretical properties than the polychoric correlation coefficient.
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| 6. |
- Eriksson, Anna, 1977-
(författare)
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Studies of New Signal Transduction Modulators in Acute Myeloid Leukemia
- 2012
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Acute myeloid leukemia (AML) is a life-threatening malignant disorder with dismal prognosis. AML is characterized by frequent genetic changes involving tyrosine kinases, normally acting as important mediators in many basic cellular processes. Due to the overexpression and frequent mutations of the FMS-like receptor tyrosine kinase 3 (FLT3) in AML, this tyrosine kinase receptor has become one of the most sought after targets in AML drug development.In this thesis, we have used a combination of high-throughput screens, direct target interaction assays and sequential cellular screens, including primary patient samples, as an approach to discover new targeted therapies. Gefitinib, a previously known inhibitor of epidermal growth factor receptor and the two novel tyrosine kinase inhibitors AKN-032 and AKN-028, have been identified as compounds with cytotoxic activity in AML.AKN-028 is a potent inhibitor of FLT3 with an IC50 value of 6 nM in an enzyme assay, but also displaying in vitro activity in a variety of primary AML samples, irrespective of FLT3 mutation status or quantitative FLT3 expression. AKN-028 shows a sequence dependent in vitro synergy when combined with standard cytotoxic agents cytarabine or daunorubicin, with better efficacy when cells are exposed to standard chemotherapy simultaneously or for 24 hours prior to adding AKN-028. Antagonism is observed when cells are pre-treated with AKN-028, possibly explained by the cell cycle arrest induced by the compound. In vivo cytotoxic activity and good oral bioavailability have made AKN-028 a candidate drug for clinical studies and the compound is presently investigated in an international two-part multicenter phase I/II study.Results from microarray studies performed to further elucidate the mechanism of action of AKN-028, revealed significantly altered gene expression induced by AKN-028 in both AML cell lines and in primary AML cells, with an enrichment of the Myc pathway among the downregulated genes.Furthermore, tyrosine kinase activity profiling shows a dose-dependent kinase inhibition by AKN-028 in all AML samples tested. Interestingly, cells with a high overall kinase activity were more sensitive to AKN-028. Provided conformation in a larger set of samples, kinase activity profiling may give useful information in individualizing treatment of patients with AML.
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| 7. |
- Eriksson, Mats
(författare)
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Från ingenjörskonst till informatörskonst : studier av PR och riskkommunikation
- 2003
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- This thesis discusses the external risk communication of industrial companies. Such risk communication is here viewed as a division of the companies’ PR operations. There are some central weak points in current risk communication research. Up to now, this research has been dominated by a psychometric perspective and is to a great degree perception-oriented and lacking in a wider organisational perspective. A means for reaching a deeper understanding of the importance of organisational aspects in risk communication is to seek theoretical influences outside the traditional risk communication research. In this study, the two adjacent research areas of risk communication and public relations are thus cross-fertilised for the purpose of making such a knowledge contribution.The aim of the study is to examine the importance of the organisational conditions for the management of risk communication as well as to study how risk communication is developed over time. This is effected in the form of a critical analysis by the productivity of Grunig’s PR theory for the risk communication field, applied on empirical findings collected from four companies in the risk management industry (Swedish Nuclear Fuel and Waste Management Co., Rohm and Haas Nordiska, Preem Raffinaderi and Skandinaviska Raffinaderi). The study uses qualitative and comparative case studies, where the empirical data has been collected through interviews and document studies.To summerise the result of the different case studies, I make the following conclusion: (1) The internal-organisational conditions are of great importance to the way in which PR and risk communication is managed and developed. (2) A more mechanical structure and authoritarian attitude towards employees and the public give primarily asymmetrical techniques, methods and strategies (3) A more organic structure and egalitarian attitude give both asymmetrical and symmetrical communication in the proactive work. (4) When development of PR and risk communication is underway, messages are changed longitudinally from being based on facts and positive arguments to more obvious offers of exchange, ethical appeals and invitations to dialogue. (5) When PR and risk communication make for higher levels on the risk communication ladder, prevailing notions and structures in the organisation are also renegotiated.The thesis concludes that Grunig’s theory in some way is productive for risk communication, but it also points out several weak things in Grunig’s concept. Among other things, these concern the fact that the causal thinking about the link between the organisational conditions and the communicative strategies to a high degree appear as circular reasoning. The theory’s division between authoritarian and egalitarian oriented cultures is also debateable as it to a great degree only focuses on instrumental values in the organisation. Even the distinction between asymmetrical and symmetrical communication can be criticised, among other things due to vague operationalisation and its one-dimensional character.In order to develop the organisational dimension of risk communication, a more symbolistic perspective is proposed. The symbolistic perspective signifies, among other things, a more distinct integration of the internal and the external as well as the informal (imaginary) and formal (physical) within the organisations. In addition, the symbolistic perspective reduces the importance of the causal thinking in the Grunig theory and its central distinction between asymmetry and symmetry becomes less important. Instead, the focus is increasingly on the rhetoric and symbolism with leaders, communicators and in information material etc.
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| 8. |
- Faxälv, Lars, 1977-
(författare)
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Imaging methods for haemostasis research
- 2009
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Blood is a vital part of the human physiology; a transport system that brings nutrients and oxygen to sustain living cells and simultaneously facilitates the removal of carbon dioxide and other waste products from the body. To assure the continuity of these functions, it is of uttermost importance to keep the flowing blood inside the vascular system at any cost. The principal components of the haemostatic system are the blood platelets and the plasma coagulation system, both working in concert to create a blood stopping haemostatic plug when a vessel is ruptured. In modern health care, methods for treatment and diagnostics often implicate the contact between blood and artificial materials (biomaterials). Biomaterial surfaces may activate platelets and the coagulation cascade by exposing a surface that during blood contact shares certain characteristics with surfaces found at the site of vascular injury. Therefore it is of great importance that the mechanisms behind the interactions between foreign surfaces and blood are studied in order to minimize, and if possible, prevent unnecessary reactions that may lead to thrombosis.This thesis describes two important methods to study blood – surface interactions in terms of surface induced plasma coagulation and platelet adhesion/aggregation. The method ‘Imaging of coagulation’, a coagulation assay based on time-lapse image capture of the coagulation process was developed during the course of this work. The use of images enables the method to answer questions regarding where coagulation was initiated and how fast coagulation propagates. Such questions are highly relevant in the study of blood-biomaterial interactions but also in general haemostasis research. In vivo, platelet adhesion and aggregation are events that always proceed under flow conditions. Therefore we also developed a cone-and-plate flow model to study these mechanisms under similar conditions in vitro. The cone-and-plate setup was found to be a flexible platform and was used for both blood compatibility testing of potential biomaterials as well as for general haemostasis research.With the above mentioned methods we tested the haemocompatibility of glycerol monooleate (GMO), a proposed substance for use in biomaterial applications. It was found that GMO did not activate coagulation to any great extent either in plasma or in whole blood.Surface induced coagulation and platelet adhesion was also studied on PEG-containing hydrogels and compared with hydrogels constructed from three different non-PEG-containing monomers. It was concluded that all the grafted hydrogels, in particular those produced from the monomers 2-hydroxyethyl methacrylate (HEMA) and/or PEG- methacrylate (PEGMA), demonstrated good haemocompatibility.Supported phospholipid bilayers were used to investigate the relationship between surface charge and procoagulant activity. The coagulation process was studied in a straightforward manner using the imaging of coagulation setup. We concluded that the content of negatively charged 1-palmitoyl-2-oleoyl-sn-glycero-3-[phospho-L-serine] (POPS) in the bilayer must exceed ~ 6% for the bilayer to exert procoagulant activity.The physiological role of factor XII in human haemostasis and thrombosis was investigated in the imaging of coagulation setup and the cone and plate setup by the use of surfaces with thrombogenic coatings. We found that tissue factor initiated coagulation could be greatly accelerated by the presence of contact activating agents in a platelet dependent manner.In conclusion, the method ‘Imaging of coagulation’ and platelet adhesion/aggregation in the cone-and-plate flow model are both versatile methods with many possible applications. The combination of the two methods provides a solid foundation for biomaterial and haemostasis research.
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| 9. |
- Gullbo, Joachim, 1971-
(författare)
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Preclinical Development of New Alkylating Oligopeptides for Cancer Therapy
- 2003
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Oligopeptides can be used to carry cytotoxic agents in cancer chemotherapy, using tumour-associated proteins as the molecular target for selectivity. During the seventies and eighties Peptichemio, a cocktail of six alkylating oligopeptides carrying m-L-sarcolysin, was investigated in a wide variety of human malignancies. Positive clinical results were suggested to result from rapid and effective DNA-crosslinking following uptake in neoplastic cells, but also from antimetabolic properties of the drug. Although m-L-sarcolysin never reached widespread clinical use, the well established para-isomer melphalan still, after nearly fifty years, has a place in cancer chemotherapy.The present study was undertaken to synthesise the melphalan containing analogue of the tripeptide P2 (L-prolyl-m-L-sarcolysyl-p-L-fluorophenylalanine ethyl ester, the main contributor to Peptichemio’s activity) and similar compounds, preferably dipeptides. The new compounds compared favourably with melphalan, m-L-sarcolysin and P2, considering their potency in vitro. Structure activity relationship analysis showed that the activity of melphalan dipeptides depended on the amino acid composition, sequence and end group modifications, but only to a minor degree on lipophilicity. Results suggested that the dipeptides, to exert their full cytotoxic activity, had to interact with specific biomolecules such as dipeptide transporters or peptidases. Although no active transport could be demonstrated the influence of peptide hydrolysis was obvious, thereby suggesting a rationale for increased activity as well as potential tumour selectivity in comparison with melphalan.Preliminary in vivo studies in mice supported the results, despite equal alkylating capacity the dipeptide J1 (melphalanyl-p-L-fluorophenylalanine ethyl ester) and the tripeptide J3 (L-prolyl-melphalanyl-p-L-fluorophenylalanine ethyl ester) were more active than was melphalan on human tumour cells implanted in test animals although all drugs produced expected side effects, notably leukopenia, of similar magnitude.In conclusion, oligopeptide derivatives of melphalan seem to provide improved cytotoxic activity and therapeutic index. Further development of such oligopeptides for clinical use seems worthwhile.
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| 10. |
- Haglund, Caroline, 1981-
(författare)
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Integrating Efficacy and Toxicity in Preclinical Anticancer Drug Development : Methods and Applications
- 2011
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Preclinical testing is an important part of cancer drug development. The aim of this thesis was to establish and evaluate preclinical in vitro methods useful in the development of new anticancer drugs. In paper I, the development of non-clonogenic assays (FMCA-GM) using CD34+ stem cells for assessment of haematological toxicity was described. A high correlation was seen when comparing the 50% inhibitory concentrations (IC50) from FMCA-GM with the IC50 from the established clonogenic assay (CFU-GM). In paper II, FMCA-GM was complemented with additional cell models, establishing a normal cell panel. In vitro toxicity towards the five normal cell types was compared with known clinical adverse event profiles. The normal cell panel roughly reflected the tissue specific toxicities but was most useful in the prediction of therapeutic index. In paper III the use of peripheral blood lymphocytes from human, dog, rat and mouse to detect species differences in cellular drug sensitivity was described. Good agreement between our method and the established CFU-GM assay was observed. In paper II the benefit of using primary tumour cells from patients to predict cancer diagnosis-specific activity was studied. The in vitro activity of fourteen anticancer drugs was tested in tumour samples of both haematological and solid tumour origin. In general, clinical activity was well reflected. In paper IV, the efficacy and toxicity models were applied for experimental follow-up of a novel inhibitor of the ubiquitin-proteasome system, CB3 (Phosphoric acid, 2,3-dihydro-1,1-dioxido-3-thienyl diphenyl ester). In the preliminary characterization of CB3, antitumour activity and a favourable toxicity profile were displayed, although the exact mechanism of action remains to be elucidated. CB3 will therefore be further investigated. In conclusion, the work presented here contributes to different parts of the preclinical drug development and the methods may aid in the characterization of anticancer compounds
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