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This thesis contributes to the research area of causal inference, where estimation of the effect of a treatment on an outcome of interest is the main objective. Some aspects of the estimation of average causal effects in observational studies in general, and case-control studies in particular, are explored. An important part of estimating causal effects in an observational study is to control for covariates. The first paper of this thesis concerns the selection of minimal covariate sets sufficient for unconfoundedness of the treatment assignment. A data-driven implementation of two covariate selection algorithms is proposed and evaluated. A common sampling scheme in epidemiology, and when investigating rare events, is the case-control design. In the second paper we study estimators of the marginal causal odds ratio in matched and independent case-control designs. Estimators that, under a logistic regression model, utilize information about the known prevalence of being a case is examined and compared through simulations. The third paper investigates the particular situation where case-control sampled data is reused to estimate the effect of the case-defining event on an outcome of interest. The consequence of ignoring the design when estimating the average causal effect is discussed and a design-weighted matching estimator is proposed. The performance of the estimator is evaluated with simulation experiments, when matching on the covariates directly and when matching on the propensity score. The last paper studies the effect of type 1 diabetes mellitus (T1DM) on school achievements using data from the Swedish Childhood Diabetes Register, a population-based incidence register. We apply theoretical results from the second and third papers in the estimation of the average causal effect within the T1DM population. A matching estimator that accounts for the matched case-control design is used.

Adolescensutvecklingen är en känslig period, då övergången från att vara ett beroende barn till att bli en självständig vuxen skall äga rum. Under denna kritiska process sker identitetsutveckling och strävan efter att vara oberoende föräldrar ökar. År 2013 rapporterades att cirka 50000 personer i Sverige har typ 1 diabetes mellitus (T1DM) och statistik pekar på en ständig ökning av sjukdomen. T1DM är en ämnesomsättningssjukdom som kännetecknas av brist på hormonet insulin. Sjukdomen behandlas med insulin, kost och motion och kräver dessutom regelbundenhet och daglig egenvård. Syftet med studien var att identifiera hälsorelaterade utmaningar med T1DM under adolescensutvecklingen, ur ett personperspektiv. Studien är utförd som en litteraturstudie där 13 vetenskapliga artiklar har granskats och bearbetats. Resultatet visar att T1DM under adolescensutvecklingen medför speciella utmaningar och problematik kring föräldrarelationen, vikten av kunskap och stöd samt behovet av att vara som alla andra. Vidare forskning bör fokusera på föräldrars samt hälso- och sjukvårdspersonals perspektiv kring T1DM under adolescensutvecklingen, för att få ett helhetsperspektiv och kunna stödja den drabbade ungdomen på bästa sätt. / The adolescence is a sensitive period with the transition from being a dependent child to becoming an independent adult. During this critical process ones identity develops and the desire to be self-sustaining without parents increases. In 2013 it was reported that approximately 50 000 people in Sweden have type 1 diabetes mellitus (T1DM) and statistics point to a steady increase of the disease. T1DM is a metabolic disease characterized by a lack of the hormone insulin. The disease is treated with insulin, diet and exercise and also requires regularity and daily self-care. The purpose of this study was to identify health related challenges with T1DM during the period of adolescence, from a person perspective. This is a literature study in which 13 scientific articles have been reviewed and processed. The result shows that T1DM during the period of adolescence poses special challenges and problems relating to the parental relationship, the importance of knowledge and support, and the need to be like everyone else. Further research should focus on the perspectives of both parents and healthcare staff on T1DM during adolescence, to get an overall perspective and be able to assist the affected youth in the best possible way.

Aerobic exercise interventions involving individuals with type 1 diabetes have had little positive effect on blood glucose control as reflected by hemoglobin A1c. The few existing interventions involving resistance exercise, either alone or combined with aerobic exercise, while small in sample size, have had better outcomes. The purpose of this research program was to examine the changes in blood glucose levels during activity and for 24 hours post-exercise (as measured by continuous glucose monitoring) when resistance exercise is performed, either on its own or combined with aerobic exercise, as compared to aerobic exercise alone or no exercise. Twelve physically active individuals with type 1 diabetes performed 5 separate exercise sessions in random order separated by at least five days: 1) no exercise/control; 2) aerobic exercise (45 minutes of treadmill running at 60% VO2peak); 3) resistance exercise (45 minutes of weight lifting – 3 sets of 8 repetitions of 7 different exercises); 4) aerobic then resistance exercise (2 and 3 combined with the aerobic exercise first); 5) resistance then aerobic exercise (2 and 3 combined with the resistance exercise first). We found that resistance exercise was associated with a lower risk of hypoglycemia during exercise, less carbohydrate intake during exercise, less post-exercise hyperglycemia and more frequent (but less severe) nocturnal hypoglycemia than aerobic exercise. When aerobic and resistance exercise were combined, performing resistance exercise prior to aerobic exercise (rather than the reverse) resulted in attenuated declines in blood glucose during aerobic exercise, accompanied by a lower need for carbohydrate supplementation during exercise and a trend towards milder post-exercise nocturnal hypoglycemia.

Type 1 diabetes (T1D) is an autoimmune disease whereby the insulin-producing β-cells of the pancreas are destroyed by the immune system, possibly related to an inappropriate immune reaction to dietary antigens and/or microbes in the gut. We previously observed a deficit in gut-resident CD163+ M2 anti-inflammatory macrophages in BioBreeding diabetes-prone (BBdp) rats. Heme oxygenase-1 (HO-1) is the rate-limiting enzyme of the CD163 pathway and through the breakdown of toxic heme releases potent antioxidants. We hypothesized that the treatment of animals with cobalt protoporphyrin (CoPP), an inducer of HO-1 expression, would inhibit development of T1D through modulation of the CD163/HO-1 pathway and increase M2 macrophages. HO-1 expression was significantly increased in the pancreas and gut. T1D incidence was inhibited in CoPP-treated rats and these animals showed an unexpected increase in cells expressing CD68 (an M1 pro-inflammatory macrophage marker) in the pancreas and gut. CoPP induced the expression of cathelicidin anti-microbial peptide (CAMP) in the jejunum, which co-localized with CD163+ (M2) macrophages. KLF4, an M2 macrophage-specific transcription factor, was significantly upregulated in the pancreas and jejunum of CoPP-treated animals and co-localized with CD68 and HO-1 in the pancreas. We conclude that HO-1 induction prevented T1D through modulation of the gut immune system and potential recruitment of a unique population of anti-inflammatory M2 macrophages in the gut and pancreas

Over the past twenty years the incidence of both childhood acute lymphoblastic leukaemia (ALL) and type 1 diabetes have risen in many developed countries, including New Zealand. Although the explanations for this increase and the precise aetiology of both diseases remain unclear, environmental factors are thought to be important. One factor receiving increasing attention is the role of infections introduced through population mixing. However, previous studies on this topic show mixed results and population mixing itself tends to be under-theorised. Furthermore, this issue has not been adequately assessed in New Zealand, a country characterised by high levels of population mobility. In this research, a variety of population mixing measures for small areas in New Zealand were developed. National data on ALL registrations were obtained from the New Zealand Cancer Registry, and regional type 1 diabetes data were obtained from the Canterbury Diabetes Register for the Canterbury Region of the South Island. The analyses were undertaken in three stages. First, standardised incidence ratios of each disease were examined at different geographical and temporal scales, between areas of differing socioeconomic status, and in urban and rural New Zealand. Second, cluster analysis was employed to test for spatial-temporal clustering of the two diseases. Finally, multivariate regression analyses were utilised to investigate the association between each disease and the various measures of population mixing at the area-level. The results reveal similarities in the geographical epidemiology of childhood ALL and type 1 diabetes in New Zealand. The majority of the findings were suggestive of an infectious aetiology for both diseases. In addition, higher incidence of both diseases was observed in areas which increased the most in population mixing over short time periods (6/7 years). Furthermore, raised type 1 diabetes incidence was also associated with high population mixing in early life.

Diss. (sammanfattning) Stockholm : Karolinska institutet, 2007. / Härtill 4 uppsatser.

Diss. (sammanfattning) Stockholm : Karolinska institutet, 2007. / Härtill 4 uppsatser.

Diss. (sammanfattning) Stockholm : Karol. inst., 2005. / Härtill 3 uppsatser.

Diss. (sammanfattning) Linköping : Linköpings universitet, 2008. / Härtill 4 uppsatser.