| 1. |
- Karlsson, Kristin E, 1975-
(författare)
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Benefits of Pharmacometric Model-Based Design and Analysis of Clinical Trials
- 2010
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Quantitative pharmacokinetic-pharmacodynamic and disease progression models are the core of the science of pharmacometrics which has been identified as one of the strategies that can make drug development more effective. To adequately develop and utilize these models one needs to carefully consider the nature of the data, choice of appropriate estimation methods, model evaluation strategies, and, most importantly, the intended use of the model. The general aim of this thesis was to investigate how the use of pharmacometric models can improve the design and analysis of clinical trials within drug development. The development of pharmacometric models for clinical assessment scales in stroke and graded severity events, in this thesis, show the benefit of describing data as close to its true nature as possible, as it increases the predictive abilities and allows for mechanistic interpretations of the models. Performance of three estimation methods implemented in the mixed-effects modeling software NONMEM; 1) Laplace, 2) SAEM, and 3) Importance sampling, applied when modeling repeated time-to-event data, was investigated. The two latter methods are to be preferred if less than approximately half of the individuals experience events. In addition, predictive performance of two validation procedures, internal and external validation, was explored, with internal validation being preferred in most cases. Model-based analysis was compared to conventional methods by the use of clinical trial simulations and the power to detect a drug effect was improved with a pharmacometric design and analysis. Throughout this thesis several examples have shown the possibility of significantly reducing sample sizes in clinical trials with a pharmacometric model-based analysis. This approach will reduce time and costs spent in the development of new drug therapies, but foremost reduce the number of healthy volunteers and patients exposed to experimental drugs.
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| 2. |
- Friberg, Lena E
(författare)
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Pharmacokinetic-Pharmacodynamic Modelling of Anticancer Drugs : Haematological Toxicity and Tumour Response in Hollow Fibres
- 2003
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Established quantitative relationships between dose, plasma concentrations and response [pharmacokinetic-pharmacodynamic (PKPD) models] have a high potential in improving therapeutic indices of anticancer drug therapy and in increasing drug development efficiency. PKPD modelling is a helpful tool for characterising and understanding schedule dependence. The aim of this thesis was to develop PKPD models of anticancer drugs for tumour effects and haematological toxicity, which is the most frequent dose-limiting toxicity.PK and haematological toxicity after several schedules were studied in rats and semi-physiological PKPD models for the whole time course of myelosuppression were developed from animal and patient data. The possibility to implant hollow fibres filled with tumour cells in immunocompetent rats was investigated for simultaneous assessment of PK, tumour response and haematological toxicity. Population data analyses were performed using the software NONMEM. When all injections were administered within eight hours, fractionated schedules of 5-fluorouracil and epirubicin produced similar haematological toxicity in rats as a single dose, when the non-linear PK of 5-fluorouracil was accounted for. When the time interval was extended to two days for 5-fluorouracil, the fractionated regimens were more toxic. The developed semi-physiological PKPD models included transit compartments that mimic maturation stages in bone marrow and explain the time lag. Feedback mechanisms characterised the rebound. The models successfully described myelosuppression in patients (DMDC) and rats (5-fluorouracil), after different administration schedules. Further developments made it possible to characterise the time course of myelosuppression after administration of each one of six different drugs, with parameters related to the haematopoietic system consistent across drugs. The developed hollow fibre model in immunocompetent rats was successfully applied to monitor PK, toxicity and the time course of antitumour effects. PKPD modelling illustrated that the schedule dependence of the anticancer agent CHS 828 is partly due to dose-dependent bioavailability and partly due to a schedule-dependent PD effect.
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| 3. |
- Karlsson, Fredrik, 1975-
(författare)
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The acquisition of contrast : a longitudinal investigation of initial s+plosive cluster development in Swedish children
- 2006
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- This Thesis explores the development of word-initial s+plosive consonant clusters in the speech of Swedish children between the ages of 1;6 and 4;6. Development in the word-initial consonant clusters is viewed as being determined by 1) the children’s ability to articulate the target sequence of consonants, 2) the level of understanding of which acoustic features in the adult model production are significant for the signalling of the intended distinction, and 3) the children’s ability to apply established production patterns only to productions where the acquired feature agrees with the adult target, to achieve a contrast between rival output forms. This Thesis employs a method where output forms are contrasted with attempted productions of potential homonym target words. Thus, development is quantified as an increase in the manifestations of phonetic features where it agrees with the adult norm, coupled by a decrease in the same feature in output forms where it is inappropriate according to the specifications of the phonological system of the ambient language. Acoustic investigations of cues of voicing, aspiration, place of articulation and syllable onset complexity, and auditory investigations of place, manner and syllable onset complexity were conducted. The Thesis has four outcomes. One, a description of the perceptual quality of the productions in terms of place, manner, voicing and syllable onset complexity is presented. Two, a developmental sequence of stable acquisition of these features is proposed; manner is shown to be acquired first, followed by syllable onset complexity and place of articulation. Evidence is provided that the voiced/aspirated distinction is still being acquired at the end of the investigated age period. Three, the developmental use of acoustic cues of place and voicing are described. Voice Onset Time and Spectral Skewness are shown to be used by children in order to increase the likeness to the adult target in terms of voicing and place of articulation. Aspiration Amplitude is shown to be used as an auxiliary cue to Voice Onset Time. The place cues Spectral Tilt Change, F2, Spectral Mean and Spectral Variance were shown to be used in order to refine already produced consonants rather than approach the adult target model. Four, the Thesis provides evidence of periods of confusions in the output of children. With the reductions of these patterns of confusion, evidence is provided of children’s re-organisation of their internal representation of the consonant to be produced.
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| 4. |
- Karlsson, Mattias E.
(författare)
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Fundamentals of Polyethylene Composites for HVDC Cable Insulation – Interfaces and Charge Carriers
- 2020
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Power transmission over long distances by using high voltage direct current (HVDC) cables is important for the transition from fossil energy to using renewable energy sources, e.g. wind, solar and water. Higher operating voltages enable longer transmission lines but better insulation materials with a much lower conductivity than today´s crosslinked polyethylene (PE) are required to reach the goal of 1 MV by 2030. Nanocomposites consisting of small fractions of metal oxide nanoparticles in PE are promising insulation materials, showing ca. 100 times lower conductivity. The reasons for the better insulating properties are however not fully understood.The properties of PE and inorganic nanoparticles were studied in this project to evaluate the influence of different material parameters on the conductivity of the cable insulation material. For pristine PE, the polymer morphology and oxidation were found to have a significant impact on the conductivity. For PE nanocomposites, the particle/polymer interface was shown to adsorb polar molecules, which are present in PE cable insulation. A suggested hypothesis is that the adsorption on particle surfaces results in cleaning of the bulk polymer from impurities, which in turn contributes to decreased nanocomposite conductivity. Since the particle interface is believed to be decisive for the nanocomposite properties, the role of particle terminations was investigated in detail. Oxygen dominated particle terminations resulted in 2 times higher composite conductivity than with zinc dominated surfaces, while fully oxygen covered surfaces showed 10 times higher conductivity. Composite systems with micro-sized particles allowed for evaluating parameters independently, which is not possible for nanocomposites. Terminations of ‘PE-like’ hydrocarbon chains lowered the conductivity and these trends could also be transferred to similar zinc oxide nanocomposite systems.
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| 5. |
- Karlsson, Maria G. E.
(författare)
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The Importance of Cell-Mediated Immunity for the Development of Type 1 Diabetes
- 2000
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Background Type I (insulin-dependent) diabetes mellitus is an autoimmune disease characterised by infiltration of T-lymphocytes in the islets of Langerhans. In particular, activated Th1-like lymphocytes secreting IFN-γ are suggested to contribute to the inflammatory process and the destruction of ß-cells, whereas Th2-like cells producing IL-4 might even be protective. Environmental factors (diet, viruses, stress etc.) and autoantigens, e.g. Glutamic Acid Decarboxylase (GAD65) and insulin, are suggested to initiate the autoimmune process resulting in type I diabetes.Aim To estimate the immunological balance of Th1/Th2-like lymphocytes, spontaneously and after stimulation with antigens, in high-risk first degree relatives of type 1 diabetic children and in children with newly diagnosed type 1 diabetes.Materials and methods Peripheral blood mononuclear cells (PBMC) from healthy high-risk first-degree relatives (ICA ≥ 20) and newly diagnosed type 1 diabetic children were examined and compared with the response seen in PBMC from healthy controls matched for age and HLA-type (DR3 and/or DR4).Expression of IFN-γ and IL-4 mRNA was determined by RT-PCR or real-time RTPCR and IFN-γ and IL-4 by ELISPOT or ELISA, spontaneously and after stimulation with GAD65 , insulin, bovine serum albumin (BSA), the ABBOS-peptide and ß-lactoglobulin (ßLG). Cytokine expression and secretion was compared to the production of diabetes-associated autoantibodies and to the secretion of endogenous insulin.Results The epitope of GAD65, that mimics the Coxsackie B virus, caused increased IFN-γ mRNA expression in activated Th1-like lymphocytes from newly diagnosed diabetic children. This suggests that GAD65 might be involved in the development of type I diabetes. On the contrary, cow's milk proteins caused increased IFN-γ and IL- 4 mRNA expression in activated Th1- and Th2-like lymphocytes from both diabetic and healthy children. This does not support the hypothesis that cow's milk antigens are important for the development of type 1 diabetes.Overwhelming secretion of IFN-γ was observed in high-risk first-degree relatives of type 1 diabetic children. High-risk individuals still have the ability to change a Th1-like immune deviation into a more protective Th2-like response in the presence of GAD65 and insulin.Conclusions GAD65, but not cow's milk proteins, causes a Th1-like deviation in type 1 diabetic children. High-risk individuals are capable to deviate a Th1-like immune system into a more protective Th2-like response in the presence of autoantigens. These results can be useful in future therapeutic approaches.
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| 6. |
- Karlsson, Peter S.
(författare)
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Issues of incompleteness, outliers and asymptotics in high dimensional data
- 2011
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- This thesis consists of four individual essays and an introduction chapter. The essays are in the field of multivariate statistical analysis of High dimensional data. The first essay presents the issue of estimating the inverse covariance matrix alone and when it is used within the Mahalanobis distance in High-dimensional data. Three types of ridge-shrinkage estimators of the inverse covariance matrix are suggested and evaluated through Monte Carlo simulations. The second essay deals with incomplete observations in empirical applications of the Arbitrage Pricing Theory model and the interest is to model the underlying covariance structure among the variables by a few common factors. Two possible solutions to the problem are considered and acase study using the Swedish OMX data is conducted for demonstration. In the third essay the issue of outlier detection in High-dimensional data is treated. A number of point estimators of the Mahalanobis distance are suggested and their properties are evaluated. In the fourth and last essay the relation between the second central moment of a distribution to its first raw moment is considered in an financial context. Three possible estimators are considered and it is shown that they are consistent even when the dimension increases proportionally to the number of observations.
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| 7. |
- Karlsson Videhult, Frida, 1980-
(författare)
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Effects of early probiotic supplementation in a pediatric setting : Focus on body composition, metabolism and inflammation
- 2016
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- We aimed to determine the short- and long-term effects on growth, body composition, metabolic and inflammatory markers following supplementation with the probiotic Lactobacillus paracasei ssp. paracasei F19 (LF19) during weaning. Methods: One-hundred and seventy-nine healthy, infants in Umeå city, Västerbotten County were randomised to daily intake of cereals with (n=89) or without (n=90) LF19 108 colony-forming units from 4 to 13 months of age. Weight, length, head circumference and body composition, assessed by skinfold thickness, were examined at 4, 5.5, 6.5, 9, 12 and 13 months of age. Venous blood was drawn at 5.5 and 13 months. In all, 171 infants completed the intervention and were invited to a follow-up at 8-9 years of age between 2009 and 2011, 120 children participated. Weight, height, sagittal abdominal diameter and body composition (using Dual Energy X-ray Absorptiometry-scan) were measured. Data on weight and height at 4 years were collected from medical records. The families filled out a 4-day food record and a food frequency questionnaire, physical activity was assessed using a pedometer for 7 days. At 5.5, 13 months and 8-9 years of age we analysed the serum blood lipid profile. At 8-9 years fasting glucose, insulin, aspartate and alanine transaminases were analysed in serum. Homeostatic Model Assessment index was calculated. At follow-up serum adiponectin, high-sensitivity C-reactive protein and plasma C-peptide, ghrelin, gastric inhibitory polypeptide, glucagon-like peptide 1, glucagon, insulin, leptin, plasminogen activator inhibitor-1, resistin and visfatin were analysed. For characterisation of the plasma metabolome, a subgroup (n=40) was analysed at 5.5 and 13 months of age by gas chromatography time-of-flight mass spectrometry (GC-TOF/MS) analysis and in all (n=112) children at the follow-up using untargeted GC-GC/MS. Results: There were no differences between the LF19 and placebo group regarding body weight, length/height at any assessment from 4 months to 8-9 years of age; nor were there any differences between the groups in body composition. In the LF19 group 19 % were overweight/obese, the corresponding number was 21 % in the placebo group (p=0.78). Analysed metabolic and inflammatory markers, both during the intervention and the follow-up did not differ between the two groups. At 13 months of age lower levels of palmitic acid and palmitoleic acid (both p<0.04) and higher levels of putrescine (p<0.01) were seen in the LF19 compared to the placebo group. These differences did not persist at 8-9 years of age. At that age, we found statistically stronger models when comparing overweight/obese and normal weight children as well as in relation to sex. Conclusion: Early intervention with the probiotic LF19 at the time of weaning exerted transient effects on the metabolome. In a long-term perspective, we found neither benefit nor harm on growth, body composition, metabolic or inflammatory markers following supplementation with LF19 during weaning.
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| 8. |
- Nielsen, Elisabet I, 1973-
(författare)
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Pharmacometric Models for Antibacterial Agents to Improve Dosing Strategies
- 2011
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Antibiotics are among the most commonly prescribed drugs. Although the majority of these drugs were developed several decades ago, optimal dosage (dose, dosing interval and treatment duration) have still not been well defined. This thesis focuses on the development and evaluation of pharmacometric models that can be used as tools in the establishment of improved dosing strategies for novel and already clinically available antibacterial drugs. Infectious diseases are common causes of death in preterm and term newborn infants. A population pharmacokinetic (PK) model for gentamicin was developed based on data from a prospective study. Body-weight and age (gestational and post-natal age) were found to be major factors contributing to variability in gentamicin clearance and therefore important patient characteristics to consider for improved dosing regimens. A semi-mechanistic pharmacokinetic-pharmacodynamic (PKPD) model was also developed, to characterize in vitro bacterial growth and killing kinetics following exposure to six antibacterial drugs, representing a broad selection of mechanisms of action and PK as well as PD characteristics. The model performed well in describing a wide range of static and dynamic drug exposures and was easily applied to other bacterial strains and antibiotics. It is, therefore, likely to find application in early drug development programs. Dosing of antibiotics is usually based on summary endpoints such as the PK/PD indices. Predictions based on the PKPD model showed that the commonly used PK/PD indices were well identified for all investigated drugs, supporting that models based on in vitro data can be predictive of antibacterial effects observed in vivo. However, the PK/PD indices were sensitive to the study conditions and were not always consistent between patient populations. The PK/PD indices may therefore extrapolate poorly across sub-populations. A semi-mechanistic modeling approach, utilizing the type of models described here, may thus have higher predictive value in a dose optimization tailored to specific patient populations.
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| 9. |
- Norman-Monroe, Therese, 1984-
(författare)
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Transport accessibility, wholesale trade and spatial development
- 2017
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- This thesis comprises four independent papers, which all explore some aspect of the relationship between accessibility and spatial development. The central question I pose is how improved accessibility to transportation services, human capital, jobs, or the market contributes to the spatial variation in economic development. Empirical data and estimations are utilized in all chapters.The first paper (co-authored with Johan Klaesson) explores how a regional accessibility model can be used to analyze the growth of knowledge-intensive industries on a detailed geographical scale compared to a broader definition.In the second paper (co-authored with Maria Börjesson and Christer Anderstig), a refined accessibility measure is used to estimate the magnitude of the causal effect of transport system investments on the unemployment rate, and whether the effect differs for people with different levels of education.The third paper addresses the role that access to transportation services plays for wholesale start-ups, particularly in regions lacking in local demand.The analysis in paper number four covers the same time period as the advancement of the Internet, which greatly reduced transaction costs. The paper examines the importance of access to human capital for the spatial reorganization and growth of wholesale industries during this time period.
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| 10. |
- Quartino, Angelica L, 1979-
(författare)
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Pharmacometric Models for Improved Prediction of Myelosuppression and Treatment Response in Oncology
- 2011
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Chemotherapy plays an important role in the treatment of cancer. However, these drugs also cause death of non-malignant cells, resulting in severe side-effects. In addition, drug resistance may exist. Predictive tools for dose and drug selection are therefore warranted. In this thesis predictive pharmacometric models were developed for the main dose-limiting side-effect, neutropenia, and for treatment response following chemotherapy. Neutropenia is associated with a high risk for life-threatening infections and leads frequently to reduced dose delivery and thereby suboptimal treatment of the tumor. A better characterization of the dynamics of docetaxel induced neutropenia was obtained by simultaneous analysis of neutrophils and leukocytes. The fraction of neutrophils was shown to change over the time-course, hence leukocytes and neutrophil counts are not interchangeable biomarkers. Sometimes neutrophil count is reported as categorical severity of neutropenia (Grade 0-4). A method was developed that allowed analysis of these data closer to its true continuous nature. The main regulatory hormone of neutrophils is granulocyte colony stimulating factor (G-CSF). Although recombinant G-CSF is used as supportive therapy to prevent neutropenia, little is known of how the endogenous G-CSF concentrations vary in patients following chemotherapy. A prospective study was carried out and simultaneous analysis of endogenous G-CSF and neutrophils following chemotherapy enabled a more mechanistic model to be developed that also could verify the self-regulatory properties of the physiological system. Patient characteristics were investigated using a pharmacokinetic-myelosuppression model for docetaxel in patients with normal and impaired liver function. The model was a useful tool in evaluating different dosing strategies and a reduced dosing scheme was suggested in patients with poor liver function, thereby enabling docetaxel treatment in this patient population which has previously been excluded. Treatment of acute myeloid leukemia with daunorubicin and cytarabine is associated with drug resistance and high variability in pharmacokinetics, which was partly explained for daunorubicin by peripheral leukocyte count. An integrated model of the in vitro drug sensitivity and treatment response showed that in vitro drug sensitivity was predictive for treatment outcome in this patient population and may therefore be used for choice of drug. The developed pharmacometric models in this thesis may be useful in the optimization of treatments schedules for existing and new drugs as well as to assist in drug and dose selection to improve therapy in an individual patient. The models and methods presented may also facilitate pooled analysis of data and demonstrate principles which could be useful for the pharmacometric community.
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