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Orientadores: Carlos Alberto Petta, Denise Engelbrecht Zantut-Wittmann / Tese (doutorado) - Universidade Estadual de Campinas, Faculdade de Ciencias Medicas / Made available in DSpace on 2018-08-08T17:23:05Z (GMT). No. of bitstreams: 1 Arruda_MauriciodeSouza_D.pdf: 343806 bytes, checksum: 09bf586ba699ac3a35538ead5e7277a9 (MD5) Previous issue date: 2007 / Resumo: O objetivo deste estudo de corte transversal foi comparar a prevalência de doença tiroideana auto-imune e disfunção tiroideana entre mulheres portadoras de endometriose e um grupo de controle. Foram avaliadas 148 mulheres, com diagnóstico cirúrgico de endometriose, acompanhadas no Ambulatório de Endometriose do Centro de Atenção Integral à Saúde da Mulher da Universidade Estadual de Campinas, no período de dezembro de 2005 a abril de 2006, e comparadas a 158 mulheres atendidas no Ambulatório de Planejamento Familar da mesma intituição e no mesmo período. As pacientes foram entrevistadas durante uma de suas consultas nos respectivos Ambulatórios. Foram avaliadas: i) a função tiroideana através das dosagens dos hormônios Tiroestimulante e Tiroxina livre, e ii) a presença de doença tiroideana auto-imune através dos anticorpos anti-tiroglobulina e anti-tiroperoxidase. A associação entre as variáveis independentes, o grupo de estudo e as doenças tiroidianas foi avaliada através dos testes qui-quadrado e exato de Fisher, teste de Mann-Whitney e cálculo de odds ratio com seu respectivo intervalo de confiança 95%. A prevalência de hipotiroidismo foi de 12,2% (18 mulheres) no grupo com endometriose e 7,8% (12 mulheres) no grupo de controle (OR 1,49; IC 95%, 0,69 ¿ 3,2). A prevalência de hipotiroidismo auto-imune foi de 6,0% (9/148) e 5,0% (8/158), nos dois grupos, respectivamente (p <0,005). Identificamos 4,0% (6 mulheres) de hipotiroidismo instalado entre as mulheres com endometriose e 3,2% (5 casos) nas mulheres do grupo de controle. A prevalência de doença tiroidiana auto-imune foi de 8,8% (13/148 mulheres) entre as mulheres com endometriose e 15,8% (25/158) entre as mulheres no grupo de controle (OR 0,52; IC 95%, 0,25 ¿ 1,06). Em conclusão, os resultados obtidos neste estudo não sustentam a hipótese de que mullheres com endometriose apresentam maior prevalência de disfunção tiroidiana ou doença tiroidiana autoimune. Assim, entendemos não haver necessidade de rastreamento diferenciado para hipotiroidismo ou para disfunção tiroidiana nas mulheres com endometriose / Abstract: The objective of this cross sectional study was to compare the prevalence of autoimmune thyroid disease and thyroid dysfunction between women with endometriosis and a control group. One hundred forty eight women with surgically confirmed endometriosis attended at the endometriosis outpatient clinic at the Department of Obstetrics and Gynaecology, School of Medicine, Universidade Estadual de Campinas (Unicamp) were evaluated from December 2005 to April 2006 and compared to 158 women from the family planning outpatient clinic at the same institution, during the same time period. All patients were interviewed in one of their regular visit. Thyroid function and autoimmunity were evaluated by measuring serum level of thyroid stimulating hormone, free thyroxin and the antibodies antithyroperoxidase and antithyroglobulin. The association of independent variables and the study group with thyroid disorder and with thyroid dysfunction was assessed by X2 test and Fisher test. Prevalence of thyroid disorders and thyroid dysfuncion among women with endometriosis were calculated and compared with the control group using Mann-Whitney test and the odds ratio was calculated with the 95% confidence interval. The prevalence of hypothyroidism was 12.2 % (18 women) among women with endometriosis and 7.8% (12 women) in the control group (OR 1.49; CI 95%, 0.69 ¿ 3.23). The prevalence of autoimmune hypothyroidism was 6% (9/148) and 5% (8/158) in both groups, respectively. We identified 4% (6 women) with overt hypothyroidism in the group of women with endometriosis and 3.2% (5 cases) among women from the control group. The prevalence of autoimmune thyroid disease was 8.8 % (13 women) among women with endometriosis and 15.8% (25 women) in the control group (OR 0.52; CI 95%, 0.25 ¿ 1.06). Our data do not support the hypotesis that women with endometriosis present a higher prevalence of autoimmune thyroid disease or thyroid dysfuction. Therefore, we believe there is no need for a specific screening of thyroid diseases among women with endometriosis / Doutorado / Tocoginecologia / Doutor em Tocoginecologia

Thyroid hormone is a master regulator of growth and development in all vertebrates. Thus, disruption of its synthesis and activity can lead to profound consequences. Past decade studies on thyroid function tests have established an efficient guideline for monitoring thyroid diseases, yet a significant proportion of healthcare providers do not defer to it in their practice. The aim of this study is to assess provider practices in the diagnosis and treatment of primary hypothyroidism due to autoimmunity at Boston Children's Hospital (CHB) for a primarily pediatric patient population. Commonly known as Hashimoto's thyroiditis (HT), this is the most common thyroid disease in the world as well as the most common manifestation of human autoimmune endocrine disease. Through CHB's bioinformatics institute, a rich data set was collected to assess the manner in which healthcare providers utilized relevant thyroid function tests (TFTs). This work assessed and confirmed the superior sensitivity of thyroid peroxidase autoantibodies (TPO) relative to thyroglobulin antibodies (TgAb) for diagnosing HT in children. We also verified proper utilization of thyroid stimulating hormone tests to monitor HT but concluded that there is a low utilization efficiency with regards to measurements of thyroid hormones (thyroxine and triiodothyronine). Based upon the observation of unnecessary monetary loss caused by improper TFTs utilization, it can be concluded that reflex testing at CHB may improve provider practices' efficiency for HT monitoring.

The population of northern Sweden has previously been shown to be well suited for the mapping of monogenic diseases. In this thesis we have tested the hypothesis that this population could also be used for efficient identification of risk genes for common diseases. In Paper I we have hypothesised that despite the admixture of Swedish, Finnish and Sami, the northern Swedish population consists of sub-populations geographically restricted by the main river valleys running through the region. This geographic isolation, in combination with founder effects and genetic drift, could represent a unique resource for genetic studies. On the other hand, it also underlines the importance of accounting for this e.g. in genetic association studies. To test this hypothesis, we studied the patterns of marriage within and between river valley regions and compared allelic frequencies of genetic markers between these regions. The tendency to find a spouse and live in the river valley where one was born is strong, and allelic frequencies of genetic markers vary significantly between adjacent regions. These data support our hypothesis that the river valleys are home to distinct sub-populations and that this is likely to affect mapping of genetic diseases in these populations. In Paper II, we tested the applicability of the population in mapping HSAN V, a monogenic disease. This disease was identified in only three consanguineous individuals suffering from a severe loss of deep pain perception and an impaired perception of heat. A genome-wide scan combined with sequencing of candidate genes resulted in the identification of a causative point mutation in the nerve growth factor beta (NGFB) gene. In Paper III, a large family with multiple members affected by familial forms of type 1 diabetes mellitus (T1DM) and autoimmune thyroiditis (AITD) was studied. This syndrome was mapped to the IDDM12 region on 2q33, giving positive lodscores when conditioning on HLA haplotype. The linkage to HLA and to the IDDM12 region thus confirmed previous reports of linkage and/or association of T1DM and AITD to these loci and provided evidence that the same genetic factors may be mediating these diseases. This also supported the feasibility of mapping complex diseases in northern Sweden by the use of familial forms of these diseases. In Paper IV, we applied the same approach to study type 2 diabetes mellitus (T2DM). A non-parametric genome-wide scan was carried out on a family material from northern Sweden, and linkage was found to the calpain-10 locus, a previously described T2DM-susceptibility gene on 2q37. Together, these findings demonstrate that selecting for familial forms of even complex diseases, and choosing families from the same geographical region can efficiently reduce the genetic heterogeneity of the disease and facilitate the identification of risk genes for the disease.

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Modern medical practice and science involve complex phenotypic definitions. Understanding patterns of association across this range of phenotypes requires co-analysis of high-dimensional association studies in order to characterise shared and distinct elements. In this thesis I address several problems in this area, with a general linking aim of making more efficient use of available data. The main application of these methods is in the analysis of genome-wide association studies (GWAS) and similar studies. Firstly, I developed methodology for a Bayesian conditional false discovery rate (cFDR) for levering GWAS results using summary statistics from a related disease. I extended an existing method to enable a shared control design, increasing power and applicability, and developed an approximate bound on false-discovery rate (FDR) for the procedure. Using the new method I identified several new variant-disease associations. I then developed a second application of shared control design in the context of study replication, enabling improvement in power at the cost of changing the spectrum of sensitivity to systematic errors in study cohorts. This has application in studies on rare diseases or in between-case analyses. I then developed a method for partially characterising heterogeneity within a disease by modelling the bivariate distribution of case-control and within-case effect sizes. Using an adaptation of a likelihood-ratio test, this allows an assessment to be made of whether disease heterogeneity corresponds to differences in disease pathology. I applied this method to a range of simulated and real datasets, enabling insight into the cause of heterogeneity in autoantibody positivity in type 1 diabetes (T1D). Finally, I investigated the relation of subtypes of juvenile idiopathic arthritis (JIA) to adult diseases, using modified genetic risk scores and linear discriminants in a penalised regression framework. The contribution of this thesis is in a range of methodological developments in the analysis of high-dimensional association study comparison. Methods such as these will have wide application in the analysis of GWAS and similar areas, particularly in the development of stratified medicine.