Des études récentes ont montré que parmi les infections émergentes chez l'homme, env. 40% étaient des zoonoses liées à la faune sauvage. La surveillance sanitaire de ces animaux devrait contribuer à améliorer la protection de leur santé et aussi celle des animaux domestiques et des hommes. Notre objectif était de développer des outils de détection de problèmes sanitaires inhabituels dans la faune sauvage, en adoptant une approche syndromique, utilisée en santé humaine, avec des profils pathologiques comme indicateurs de santé non spécifiques. Un réseau national de surveillance des causes de mortalité dans la faune sauvage, appelé SAGIR, a fourni les données. Entre 1986 et 2007, plus de 50.000 cas ont été enregistrés, représentant 244 espèces de mammifères terrestres et d'oiseaux, et attribués à 220 différentes causes de mort. Le réseau a d'abord été évalué pour sa capacité à détecter précocement des événements inhabituels. Des classes syndromiques ont ensuite été définies par une typologie statistique des lésions observées sur les cadavres. Les séries temporelles des syndromes ont été analysées en utilisant deux méthodes complémentaires de détection : un algorithme robuste développé par Farrington et un modèle linéaire généralisé avec des termes périodiques. Les tendances séculaires de ces syndromes et des signaux correspondent a des excès de cas ont été identifiés. Les signalements de problèmes de mortalité inhabituelle dans le bulletin du réseau ont été utilisés pour interpréter ces signaux. L'étude analyse la pertinence de l'utilisation de la surveillance syndromique sur ce type de données et donne des éléments pour des améliorations futures. / Recent studies have shown that amongst emerging infectious disease events in humans, about 40% were zoonoses linked to wildlife. Disease surveillance of wildlife should help to improve health protection of these animals and also of domestic animals and humans that are exposed to these pathogenic agents. Our aim was to develop tools capable of detecting unusual disease events in free ranging wildlife, by adopting a syndromic approach, as it is used for human health surveillance, with pathological profiles as early unspecific health indicators. We used the information registered by a national network monitoring causes of death in wildlife in France since 1986, called SAGIR. More than 50.000 cases of mortality in wildlife were recorded up to 2007, representing 244 species of terrestrial mammals and birds, and were attributed to 220 different causes of death. The network was first evaluated for its capacity to detect early unusual events. Syndromic classes were then defined by a statistical typology of the lesions observed on the carcasses. Syndrome time series were analyzed, using two complimentary methods of detection, one robust detection algorithm developed by Farrington and another generalized linear model with periodic terms. Historical trends of occurrence of these syndromes and greater-than-expected counts (signals) were identified. Reporting of unusual mortality events in the network bulletin was used to interpret these signals. The study analyses the relevance of the use of syndromic surveillance on this type of data and gives elements for future improvements.

Submitted by Luciana Ferreira (lucgeral@gmail.com) on 2014-11-19T12:09:09Z No. of bitstreams: 2 Dissertação - Roberta Ribeiro Rios - 2012.pdf: 1382110 bytes, checksum: bf39296c44d43bcbbb2ab974af3fb6b4 (MD5) license_rdf: 23148 bytes, checksum: 9da0b6dfac957114c6a7714714b86306 (MD5) / Approved for entry into archive by Luciana Ferreira (lucgeral@gmail.com) on 2014-11-20T14:20:46Z (GMT) No. of bitstreams: 2 Dissertação - Roberta Ribeiro Rios - 2012.pdf: 1382110 bytes, checksum: bf39296c44d43bcbbb2ab974af3fb6b4 (MD5) license_rdf: 23148 bytes, checksum: 9da0b6dfac957114c6a7714714b86306 (MD5) / Made available in DSpace on 2014-11-20T14:20:46Z (GMT). No. of bitstreams: 2 Dissertação - Roberta Ribeiro Rios - 2012.pdf: 1382110 bytes, checksum: bf39296c44d43bcbbb2ab974af3fb6b4 (MD5) license_rdf: 23148 bytes, checksum: 9da0b6dfac957114c6a7714714b86306 (MD5) Previous issue date: 2012-09-08 / Syndromic management approach to sexually transmitted diseases consists of classifying the disease within predetermined syndromes, using flowcharts which are based on signs and symptoms establishing treatment immediately without waiting serological laboratory results for confirmation, providing at the first appointment the diagnosis, treatment and appropriate counseling, interrupting the transmission chain and avoiding the complications of sexually transmitted diseases, thus allowing immediate reversal of symptoms. But its success requires constant evaluation of the protocols, and training of professionals. OBJECTIVE: to assess the impact of in-service education on knowledge of nurses from Family Health Strategy regarding the use of the syndromic approach to sexually transmitted diseases before and after a training course. METHOD: This research was performed through the interventional study approach. The samples consisted of Brazilian Primary Care and Family Health Strategy Nurses. A survey to evaluate the knowledge about the syndromic management approach was applied before and after the education. RESULTS: 71 nurses participated in this study, and there was a significant improvement in knowledge concerning the syndromic approach (p <0.05); in relation to the identification of clinical signs, such as genital ulcers, urethral discharges and vaginal and pelvic pain, there was a significant improvement among the professionals after the training, with an increase in the percentage of 27%, 28%, 23% and 31% respectively. Regarding the prescription of drugs proposed for each syndrome, 40.84% of nurses reported performing the prescription for patients with genital ulcers, 49.30% prescribed to patients with urethral discharge, 84.5% to those with with vaginal discharge and cervicitis and only 22.53% with pelvic pain. CONCLUSION: The training of nurses has provided increased knowledge on the syndromic approach to sexually transmitted diseases. It is believed that these actions indirectly favor the reduction of the chain of transmission and spread of sexually transmitted diseases if they are being carried out with quality and effective intervention. It is therefore urgent that continuing education is effectively established at primary health care, ensuring an effective improvement of quality of care provided to patients with STDs. / A abordagem sindrômica das doenças sexualmente transmissíveis consiste em classificar a doença dentro de síndromes pré-estabelecidas, utilizando fluxogramas que se baseiam em sinais e sintomas, instituindo o tratamento imediato sem aguardar resultados de exames laboratoriais sorológicos para sua confirmação, provendo na primeira consulta o diagnóstico, o tratamento e o aconselhamento adequados, interrompendo a cadeia de transmissão e evitando as complicações advindas das doenças sexualmente transmissíveis permitindo dessa forma a regressão imediata dos sintomas, entretanto seu sucesso exige avaliação constante dos protocolos, e treinamento dos profissionais envolvidos. OBJETIVO: Avaliar o impacto das ações educativas no conhecimento de enfermeiros da Estratégia de Saúde da Família quanto à utilização da abordagem sindrômica das doenças sexualmente transmissíveis antes e após um curso de capacitação. MÉTODO: Estudo analítico e de intervenção com enfermeiros que atuam nas Unidades de Atenção Básica de Saúde da Família. Um questionário de avaliação do conhecimento sobre a abordagem sindrômica foi aplicado antes e após a educação permanente. RESULTADOS: Participaram desse estudo 71 enfermeiros, verificou-se uma melhora significativa no domínio dos conteúdos referentes à abordagem sindrômica (p<0,05 e na identificação dos sinais clínicos de úlceras genitais, corrimentos uretral e vaginal e dor pélvicacom acréscimos percentuais de 27%, 28%, 23% e 31%, respectivamente. Em relação à prescrição dos medicamentos propostos para cada síndrome 40,84% relataram realizar a prescrição para pacientes com úlceras genitais; 49,30% com corrimento uretral; 84,5% com corrimento vaginal e cervicite e apenas 22,53% com dor pélvica. CONCLUSÃO: A capacitação dos enfermeiros proporcionou uma melhora significativa do conhecimento em abordagem sindrômica de doenças sexualmente transmissíveis. Acredita- se essas ações sendo exercidas com qualidade e de forma resolutiva favorecem de maneira indireta a redução da cadeia de transmissão e a propagação de doenças sexualmente transmissíveis. Assim, torna-se relevante que a educação permanente seja efetivamente instituída na atençãol primária de saúde, garantindo uma melhora efetiva da qualidade da assistência prestada ao portador de doença sexualmente transmissível.

A complexidade da fisiologia da audição resulta da participação e interação de produtos de grande número de genes, razão pela qual a surdez hereditária exibe enorme heterogeneidade genética. Estudos moleculares nas duas últimas décadas permitiram a identificação de vários genes responsáveis por surdez; entretanto, muitos ainda restam ser identificados. A maioria dos estudos de mapeamento de genes de surdez até então conduzidos privilegiou estratégias que buscavam mutações de ponto. Outros mecanismos mutacionais, como deleções e duplicações, foram pouco investigados. Portanto, a contribuição das CNVs (Copy Number Variations) na surdez hereditária é pouco conhecida. O objetivo desse trabalho foi identificar novos genes que possam ter papel na etiologia da surdez sindrômica ou não-sindrômica por meio da investigação de microdeleções e microduplicações em pacientes com perda auditiva. Selecionamos 25 genes candidatos (CTTN, FGF3, FGF19, FOXC1, FOXF2, FOXQ1, IMMP2L, KIF5C, LRRN3, MAP1A, MYLK4, PPP3CA, SHANK2, SLC5A7, STRC, TMC1, TMC2, TMC3, TMC4, TMC5, TMC6, TMC7, TMC8, TPCN2 e TUBB2A) para a triagem de microrrearranjos por meio da técnica de MLPA (Multiplex Ligation-dependent Probe Amplification). Os genes candidatos foram selecionados a partir de rearranjos detectados em um estudo prévio realizado por meio de array-CGH (array-based Comparative Genomic Hybridization) em indivíduos com surdez sindrômica estudados em nosso laboratório, e também a partir de dados da literatura. Nossa casuística foi composta por 163 indivíduos, dos quais 74 são pacientes com surdez associada a outros sinais (sindrômicos), a maioria casos isolados, e 89 são pacientes com surdez não-sindrômica, propósitos de famílias em que segrega surdez de herança autossômica dominante ou recessiva. Desenhamos uma sonda sintética intragênica de MLPA para cada um dos genes candidatos. Foram detectadas seis deleções em TMC6 (3,7%), seis deleções e uma duplicação em STRC (4,3%) e uma duplicação em IMMP2L (0,6%). A triagem de alterações nesses três genes em 189 indivíduos fenotipicamente normais revelou quatro deleções em TMC6 (2,1%), oito deleções e três duplicações em STRC (5,8%) e três deleções em IMMP2L (1,6%). Todas as alterações em TMC6, tanto nos casos de surdez como nos controles, eram na realidade artefatos devidos a problemas de hibridação da sonda correspondente. No gene STRC, previamente já relacionado à surdez, os rearranjos nos indivíduos afetados devem se tratar de polimorfismos sem efeito fenotípico por serem muito frequentes na população. Contudo, é possível que haja nesses pacientes mutações adicionais que não puderam ser rastreadas e que poderiam contribuir ao fenótipo, em combinação com o rearranjo detectado, como já descrito em um caso da literatura. A duplicação em IMMP2L em uma paciente com surdez não-sindrômica, herdada da mãe igualmente afetada, mostrou-se a mais provavelmente relacionada ao fenótipo, pois o estudo complementar por meio de array-CGH revelou que o rearranjo inclui uma duplicação parcial da porção 3 de outro gene, DOCK4. O produto desse gene possui uma isoforma que se localiza nos estereocílios das células ciliadas e se liga a uma importante proteína relacionada à audição, a harmonina. Portanto, nossa hipótese é a de que a duplicação seja a causa da surdez na família e que DOCK4 seja um novo gene responsável por surdez. A associação de IMMP2L com surdez é menos provável devido ao grande número de CNVs não patogênicas já descritas que incluem partes desse gene. Estudos complementares são necessários para mapear a duplicação com mais precisão. Além disso, o rastreamento de mutações em DOCK4 em outras famílias com surdez pode vir a confirmar o possível papel desse gene na etiologia da surdez. / Several genes contribute to the complexity of physiology of hearing. Consequently, hereditary deafness is extremely heterogeneous from the genetic point of view. In the last two decades, several genes responsible for hereditary hearing loss have been identified, but a large number of genes remains to be found, as evidenced by the unexplained cases of inherited deafness. The search for point mutations in candidate genes after mapping based on linkage studies has been the main strategy in the identification of such genes. Other mutation mechanisms, such as deletions and duplications, have been rarely investigated, and the contribution of DNA copy number variants (CNVs) to hearing loss is not well known. This study aimed at identifying novel genes, which might play a role in the etiology of syndromic and non-syndromic deafness, through the search of gene microdeletions and microduplications. We selected 25 candidate genes (CTTN, FGF3, FGF19, FOXC1, FOXF2, FOXQ1, IMMP2L, KIF5C, LRRN3, MAP1A, MYLK4, PPP3CA, SHANK2, SLC5A7, STRC, TMC1, TMC2, TMC3, TMC4, TMC5, TMC6, TMC7, TMC8, TPCN2 and TUBB2A) based on their involvement in microimbalances detected by Array-based Comparative Genomic Hybridization (aCGH) in a previous study of a Brazilian sample of individuals with syndromic hearing loss from our laboratory and others reported in the literature. We studied 163 subjects, 74 of them presenting syndromic deafness, the majority were isolated cases, and 89 being probands of families in which nonsyndromic deafness had an autosomal dominant or recessive mode of inheritance. Gene deletions or duplications were screened by Multiplex Ligant-dependent Probe Amplification (MLPA) using one synthetic intragenic probe designed for each candidate gene. We detected six deletions in TMC6 (3,7%), six deletions and one duplication in STRC (4,3%), and one duplication in IMMP2L (0,6%). The screening of imbalances in these genes in a control sample of 189 hearing individuals revealed four deletions in TMC6 (2,1%), eight deletions and three duplications in STRC (5,8%) and three deletions in IMMP2L (1,6%). The imbalances found in TMC6, both in affected and control individuals, were in fact artifacts due to problems in the hybridization of the corresponding probe. As to the STRC gene, previously related to deafness, the imbalances are more likely to be 4 polymorphisms with no phenotypic effect. However, the possibility remains that additional undetected mutations in affected individuals contribute to their phenotype, in combination with the microrearrangement, as already reported in the literature. The duplication in IMMP2L in a non-syndromic patient, and also present in her affected mother, is most likely causative of deafness, since a complementary study performed with aCGH revealed that the rearrangement included a partial duplication of the 3 end of another gene, DOCK4. An isoform of the DOCK4 protein localizes to the stereocilia in the inner ear and interacts with harmonin, a protein already known to be involved in hearing. We hypothesize that this duplication may be the cause of deafness in the family and, this being the case, DOCK4 appears as a novel deafness gene. The causal association between IMMP2L and deafness is less plausible, because of the large number of reported non-pathogenic CNVs that include parts of this gene. Further studies are required to precisely map this duplication. In addition, the screening of mutations in DOCK4 in other families with hearing impairment is required to evaluate its possible role in the etiology of deafness.

As alterações cromossômicas estruturais associadas a fenótipos clínicos oferecem a oportunidade de identificação de genes cujas mutações possam estar determinando essas patologias, tendo em vista a possibilidade de que esses genes podem ter sido alterados pelas quebras ou ter o número de cópias modificado. Um número cada vez maior de evidências aponta para a participação de certas seqüências do genoma na formação de rearranjos cromossômicos recorrentes e não recorrentes. Neste trabalho, estudamos duas deleções cromossômicas detectadas em indivíduos com retardo mental associado a sinais clínicos. O objetivo foi determinar que mecanismos originaram esses rearranjos e como a perda ou quebra dos segmentos cromossômicos está relacionada com o fenótipo dos portadores. A caracterização das seqüências nos pontos de quebra e junção desses rearranjos é fundamental para a compreensão dos mecanismos de formação das alterações cromossômicas. A delimitação precisa dos segmentos deletados é necessária para a correlação com o quadro clínico. Para isso, este trabalho aliou o estudo cromossômico por hibridação in situ fluorescente (FISH) à análise do DNA. / Structural chromosomal alterations related to clinical phenotypes bring the opportunity to identify gene mutations determining the pathologies, because the causative genes may have been disrupted by the breaks or may have an altered number of copies. The delimitation of the segments involved in the chromosomal rearrangements is necessary for these genotype-phenotype correlations. The characterization of breakpoint and junction sequences in these chromosome alterations enables the identification of mechanisms originating them, and evidence has been produced pointing to the participation of particular genomic sequences in their formation. In this work, we studied two chromosomal deletions in patients with syndromic mental retardation, combining chromosomal analysis by fluorescent in situ hybridization (FISH) to DNA analysis. Our aim was to determine the mechanisms that originated these aberrations and how they were involved with the clinical phenotypes.

Les diarrhées syndromiques ont été décrites pour la première fois en 1994. Il s'agit d'un syndrome associant une diarrhée grave rebelle néonatale nécessitant une nutrition parentérale, une dysmorphie faciale, un retard de croissance intra-utéro, des anomalies immunitaires et une atteinte hépatique. Au cours de la décennie suivante, de nouveaux cas ont été décrits avec des dénominations variées, la plus fréquente étant : « syndrome tricho-hépato-enterique ». Du fait de la variabilité clinique et de l'absence de signe spécifique à l'examen anatomopathologique le diagnostic des Diarrhées syndromiques/Syndrome Tricho-hépato-entérique (DS/THE) est difficile. Grâce à une collaboration multicentrique, nous avons pu constituer une cohorte homogène de 15 enfants atteints et de leurs apparentés. Par analyse de liaison et recherche de régions homozygotes dans ces familles, deux régions situées respectivement en 5q et en 6p ont été caractérisées. Dans la première région, le gène TTC37 a été incriminé par la mise en évidence de 12 mutations pathogènes chez 9 des15 patients. Bien que les connaissances sur TTC37 soient fragmentaires, nous avons remarqué qu'il était parfois décrit comme étant l'orthologue de SKI3 chez la levure. SKI3 constitue, avec SKI2 et SKI8, le complexe SKI qui, en tant que cofacteur de l'exosome, intervient dans un des systèmes de dégradation des ARN. L'exploration de SKIV2L, l'orthologue humain de SKI2, chez les 6 patients négatifs pour TTC37 a permis de mettre en évidence des mutations pathogènes pour tous. Nous avons voulu mieux caractériser l'expression des sous-unités du complexe SKI humain. / The Syndromic Diarrhea has been described for the first time in 1994, as a probable congenital syndrome, associating intractable diarrhea of infancy with facial dysmorphism, intrauterine growth restriction, immunological defects and hepatic disease. Since then, several cases have been described, sometime using alternative names, the most common being the tricho-hepato-enteric syndrome. Because of the lack of pathological specific anomaly and the variation in severity of the clinical signs, the diagnosis of Syndromic diarrhea/tricho-hepato-enteric syndrome (SD/THE) remains difficult. Thanks to a multi-centric collaborative work, we have collected samples from 15 affected children and their families. Using linkage analysis and homozygosity mapping, we have isolated two regions in 5q and 6p, thus suggesting genetic heterogeneity. TTC37, a gene located in 5q, has been identified as responsible for SD/THE by the characterization of 12 non-ambiguous mutations in 9 children (out of the 15). At this time, TTC37 function was unknown but we noticed that it was reported as the putative ortholog of SKI3 (a yeast gene) which together with SKI2 and SKI8, constitutes the SKI complex. This complex is a cofactor of the exosome, a quality control RNA system. The analysis of the human ortholog of SKI2, SKIV2L, in the 6 patients negative for TTC37 mutations revealed deleterious mutations in all cases. In order to better characterize the expression of the human SKI complex sub-units, we have tested the expression of TTC37 transcript in a cDNA panel from normal tissues and found a ubiquitous expression excepted in the liver.

A perda auditiva é o defeito mais comum ao nascimento e cerca de 70 milhões de pessoas no mundo apresentam algum grau de perda auditiva. Além da alta incidência, as implicações da perda auditiva na linguagem, na cognição e no desenvolvimento emocional e social reforçam sua importância. No entanto, em grande parte dos pacientes, a causa da deficiência auditiva não é esclarecida. Nós usamos hibridação comparativa do genoma baseada em arrays (Array Comparative Genomic Hybridization aCGH) para investigar alterações no número de cópias de segmentos de DNA (Copy Number Variation CNV) em 31 indivíduos que apresentavam deficiência auditiva e sinais clínicos adicionais, mas que não puderam ser classificados em síndrome conhecida. A escolha de indivíduos sindrômicos se baseou no pressuposto de que, em média, apresentam alterações genômicas maiores e, portanto, mais provavelmente detectáveis com o uso de aCGH de 1 Mb, que era a plataforma disponível no início do projeto. CNVs não descrita em bancos de dados de indivíduos normais foram identificadas em oito pacientes, quatro delas ocorreram de novo enquanto as outras quatro foram herdadas de um genitor fenotipicamente normal. As alterações de novo definem segmentos cromossômicos que provavelmente contém genes relacionados à deficiência auditiva e sensíveis a dose, especificamente: 1q23.3-q25.2, 2q22q23, 6p25.3 e 11q13.2-q13.4. As alterações raras identificadas tanto nos pacientes quanto em um genitor normal poderiam ser um evento ao acaso, sem papel na deficiência auditiva; no entanto, a possibilidade de que essas alterações possam funcionar como fatores de predisposição não podem ser descartadas. Se considerarmos apenas as CNVs de novo como causativas dos fenótipos investigados, detectamos quatro pacientes portadores entre os 31 investigados (13%). Se considerarmos também as CNVs herdadas como possivelmente causativas, a taxa de desequilíbrios cromossômicos associados à surdez será de 26%. Esses resultados são provavelmente uma substimativa e esses números seriam possivelmente maiores com o uso de uma das plataformas de alta resolução disponíveis atualmente. Esses resultados, embora limitados, indicam que investigação por aCGH em pacientes com surdez sindrômica idiopática está entre os testes mais eficientes para detectar etiologia dos fenótipos, devendo ser incorporado à rotina no diagnóstico e aconselhamento genético. / Hearing loss is the most common congenital deficiency and about 70 million people worldwide present some degree of hearing impairment. In addition to its high incidence, hearing loss impacts language, cognition and social and emotional development. However, in a large proportion of patients, the cause of the hearing deficiency cannot be elucidated. We screened copy number changes by 1 Mb-array Comparative Genomic Hybridization (aCGH) in 31 individuals with syndromic hearing impairment whose clinical features were untypical for known disorders. The choice of evaluating syndromic rather than non-syndromic individuals was based on the assumption that they are more likely to carry larger genomic alterations which could be more easily detected by the comparatively low resolution 1 Mb aCCG, which was the available platform when this project started. Copy number changes (CNV) not documented in the database of normal individuals were detected in eight patients, four de novo imbalances and four inherited from a normal parent. The de novo alterations define candidate chromosome segments likely to harbor dosage sensitive genes related to hearing impairment, namely 1q23.3-q25.2, 2q22q23, 6p25.3 and 11q13.2- q13.4. The rare imbalances also present in normal parents might be casually associated with hearing impairment, but also have a possible role as a predisposition factor. When only the de novo CNVs were considered causative for the disease phenotypes, our study revealed relevant copy number changes in 4 patients (13%). If we also count the rare CNVs that had been inherited as possibly causative, the frequency of chromosome imbalances associated with syndromic deafness in our sample becomes 26%. These figures are probably underestimates and will probably become larger when high resolution oligoarray platforms are applied. These results indicate that aCGH is an efficient tool for defining the etiology of syndromic deafness and its use in routine diagnosis of hearing impairment and for genetic counseling is highly recommended.

Surdez e perda auditiva são termos utilizados para designar distúrbios da audição, o tipo de deficiência sensorial mais frequente em humanos e decorrente de alterações genéticas em cerca de 50% dos casos. A heterogeneidade de lócus, de alelos e de manifestações fenotípicas na surdez é impressionante. O lócus DFNB1, que contém os genes GJB2 e GJB6, é responsável por cerca de 40% dos casos de surdez não-sindrômica de origem genética, porém, variantes patogênicas em cerca de 150 genes são descritas como causa de surdez, que pode ser sindrômica ou não-sindrômica. Por permitirem o sequenciamento simultâneo de diversos genes em uma mesma análise, as técnicas de sequenciamento de nova geração têm sido empregadas para o diagnóstico molecular de condições geneticamente heterogêneas, incluindo a surdez. O objetivo desse estudo foi contribuir para o estudo da heterogeneidade genética da surdez por meio do sequenciamento de nova geração de um painel com 99 genes relacionados à perda auditiva. Indivíduos não aparentados de 91 famílias brasileiras, com provável causa genética de surdez, foram avaliados com o intuito de identificar as causas moleculares da surdez, detectar novas variantes e promover aconselhamento genético das famílias participantes do estudo. Variantes provavelmente causais foram detectadas em 41 dos 91 probandos analisados (45,1%), dos quais 34 (37,4%) apresentaram variantes patogênicas ou provavelmente patogênicas. Nos outros 7 casos, foram detectadas variantes de efeito desconhecido com elevado potencial de explicar a perda auditiva dos probandos. As taxas de detecção nos casos de provável surdez sindrômica foram de 44,4% no grupo com suspeita de síndrome de Waardenburg (4 de 9 casos) e de 61,5% no grupo com suspeita de síndrome de Usher (8 de 13 casos). Nos casos de surdez não-sindrômica, as taxas de detecção foram de 53,9% no grupo com provável surdez autossômica dominante, 35,1% no grupo com provável surdez autossômica recessiva e de 45,0 % no grupo com mais de um mecanismo de herança possível. Das 43 variantes classificadas como patogênicas ou provavelmente patogênicas detectadas nesse estudo, 15 nunca haviam sido descritas. Contribuições científicas importantes foram obtidas com a identificação de uma nova variante de perda de função no gene CEACAM16 como causa de surdez não-sindrômica autossômica recessiva e com a confirmação de uma variante no gene MYO3A como causa de surdez não-sindrômica autossômica dominante recém-descrita em famílias brasileiras. Os resultados obtidos permitiram concluir que o sequenciamento de nova geração de paineis multigênicos é uma estratégia eficaz para o estudo da heterogeneidade genética da surdez, contribuindo para a detecção de novas variantes, ampliando o conhecimento científico a respeito dos genes analisados, e para o aconselhamento genético dos indivíduos estudados e seus familiares / Deafness and hearing loss are terms used to describe hearing disorders, the most common type of sensory impairment in humans, which occurs due to genetic alterations in about 50% of cases. The heterogeneity of locus, alleles and phenotypic manifestations of deafness is striking. The DFNB1 locus, which contains the genes GJB2 and GJB6, is responsible for about 40% of cases of non-syndromic genetic hearing loss, but pathogenic variants in near 150 genes are described as causing deafness, which may be syndromic or non-syndromic. By allowing the simultaneous sequencing of several genes in the same analysis, next-generation sequencing techniques have been employed for the molecular diagnosis of genetically heterogeneous conditions, including deafness. The aim of this study was to contribute to the study of the genetic heterogeneity of deafness employing the next-generation sequencing of a panel with 99 genes related to hearing loss. Individuals from 91 unrelated Brazilian families, with a probable genetic cause for deafness, were evaluated with the purpose of identifying the molecular causes of deafness, to detect new variants and to provide genetic counseling to the families enrolled in the study. Probably causal variants were detected in 41 of the 91 probands analyzed (45.1%), of which 34 (37.4%) had pathogenic or likely pathogenic variants. In the other 7 cases, variants of unknown significance with high potential to explain the hearing loss were detected. Detection rates in cases of probable syndromic deafness were 44.4% in the group with suspected Waardenburg syndrome (4 of 9 cases) and 61.5% in the group with suspected Usher syndrome (8 of 13 cases). In cases of non-syndromic deafness, detection rates were 53.9% in the group with probable autosomal dominant inheritance, 35.1% in the group with probable autosomal recessive inheritance and 45.0% in the group with more than one possible mechanism of inheritance. Among the 43 variants classified as pathogenic or probably pathogenic detected in this study, 15 had never been described. Important scientific contributions were obtained such as the identification of a novel loss-of-function variant in the CEACAM16 gene as causing autosomal recessive non-syndromic deafness and the confirmation of a recently described variant in the MYO3A gene as causing autosomal dominant non-syndromic deafness in Brazilian families. The results obtained allowed us to conclude that next-generation sequencing of multigenic panels is an effective strategy for the study of the genetic heterogeneity of deafness, contributing to the detection of new variants, expanding scientific knowledge about the genes analyzed, and also to the genetic counseling of the individuals studied and their relatives

Background: Respiratory illnesses can have a substantial impact on population health and burden hospitals in terms of patient load. Advance warnings of the spread of such illness could inform public health interventions and help hospitals manage patient services. Previous research showed that calls for respiratory complaints to Telehealth Ontario are correlated up to two weeks in advance with emergency department visits for respiratory illness at the provincial level. Objectives: This thesis examined whether Telehealth Ontario calls for respiratory complaints could be used to accurately forecast the daily and weekly number of emergency department visits for respiratory illness at the health unit level for each of the 36 health units in Ontario up to 14 days in advance in the context of a real-time syndromic surveillance system. The forecasting abilities of three different time series modeling techniques were compared. Methods: The thesis used hospital emergency department visit data from the National Ambulatory Care Reporting System database and Telehealth Ontario call data and from June 1, 2004 to March 31, 2006. Parallel Cascade Identification (PCI), Fast Orthogonal Search (FOS), and Numerical Methods for Subspace State Space System Identification (N4SID) algorithms were used to create prediction models for the daily number of emergency department visits using Telehealth call counts and holiday/weekends as predictors. Prediction models were constructed using the first year of the study data and their accuracy was measured over the second year of data. Factors associated with prediction accuracy were examined. Results: Forecast error varied widely across health units. Prediction error increased with lead time and lower call-to-visits ratio. Compared with N4SID, PCI and FOS had significantly lower forecast error. Forecasts of the weekly aggregate number of visits showed little evidence of ability to accurately flag corresponding actual increases. However, when visits were aggregated over a four day period, increases could be flagged more accurately than chance in six of the 36 health units accounting for approximately half of the Ontario population. Conclusions: This thesis suggests that Telehealth Ontario data collected by a real-time syndromic surveillance system could play a role in forecasting health services demand for respiratory illness. / Thesis (Master, Community Health & Epidemiology) -- Queen's University, 2009-08-11 16:20:44.553

A perda auditiva é o defeito mais comum ao nascimento e cerca de 70 milhões de pessoas no mundo apresentam algum grau de perda auditiva. Além da alta incidência, as implicações da perda auditiva na linguagem, na cognição e no desenvolvimento emocional e social reforçam sua importância. No entanto, em grande parte dos pacientes, a causa da deficiência auditiva não é esclarecida. Nós usamos hibridação comparativa do genoma baseada em arrays (Array Comparative Genomic Hybridization aCGH) para investigar alterações no número de cópias de segmentos de DNA (Copy Number Variation CNV) em 31 indivíduos que apresentavam deficiência auditiva e sinais clínicos adicionais, mas que não puderam ser classificados em síndrome conhecida. A escolha de indivíduos sindrômicos se baseou no pressuposto de que, em média, apresentam alterações genômicas maiores e, portanto, mais provavelmente detectáveis com o uso de aCGH de 1 Mb, que era a plataforma disponível no início do projeto. CNVs não descrita em bancos de dados de indivíduos normais foram identificadas em oito pacientes, quatro delas ocorreram de novo enquanto as outras quatro foram herdadas de um genitor fenotipicamente normal. As alterações de novo definem segmentos cromossômicos que provavelmente contém genes relacionados à deficiência auditiva e sensíveis a dose, especificamente: 1q23.3-q25.2, 2q22q23, 6p25.3 e 11q13.2-q13.4. As alterações raras identificadas tanto nos pacientes quanto em um genitor normal poderiam ser um evento ao acaso, sem papel na deficiência auditiva; no entanto, a possibilidade de que essas alterações possam funcionar como fatores de predisposição não podem ser descartadas. Se considerarmos apenas as CNVs de novo como causativas dos fenótipos investigados, detectamos quatro pacientes portadores entre os 31 investigados (13%). Se considerarmos também as CNVs herdadas como possivelmente causativas, a taxa de desequilíbrios cromossômicos associados à surdez será de 26%. Esses resultados são provavelmente uma substimativa e esses números seriam possivelmente maiores com o uso de uma das plataformas de alta resolução disponíveis atualmente. Esses resultados, embora limitados, indicam que investigação por aCGH em pacientes com surdez sindrômica idiopática está entre os testes mais eficientes para detectar etiologia dos fenótipos, devendo ser incorporado à rotina no diagnóstico e aconselhamento genético. / Hearing loss is the most common congenital deficiency and about 70 million people worldwide present some degree of hearing impairment. In addition to its high incidence, hearing loss impacts language, cognition and social and emotional development. However, in a large proportion of patients, the cause of the hearing deficiency cannot be elucidated. We screened copy number changes by 1 Mb-array Comparative Genomic Hybridization (aCGH) in 31 individuals with syndromic hearing impairment whose clinical features were untypical for known disorders. The choice of evaluating syndromic rather than non-syndromic individuals was based on the assumption that they are more likely to carry larger genomic alterations which could be more easily detected by the comparatively low resolution 1 Mb aCCG, which was the available platform when this project started. Copy number changes (CNV) not documented in the database of normal individuals were detected in eight patients, four de novo imbalances and four inherited from a normal parent. The de novo alterations define candidate chromosome segments likely to harbor dosage sensitive genes related to hearing impairment, namely 1q23.3-q25.2, 2q22q23, 6p25.3 and 11q13.2- q13.4. The rare imbalances also present in normal parents might be casually associated with hearing impairment, but also have a possible role as a predisposition factor. When only the de novo CNVs were considered causative for the disease phenotypes, our study revealed relevant copy number changes in 4 patients (13%). If we also count the rare CNVs that had been inherited as possibly causative, the frequency of chromosome imbalances associated with syndromic deafness in our sample becomes 26%. These figures are probably underestimates and will probably become larger when high resolution oligoarray platforms are applied. These results indicate that aCGH is an efficient tool for defining the etiology of syndromic deafness and its use in routine diagnosis of hearing impairment and for genetic counseling is highly recommended.

La dématérialisation des données de santé a permis depuis plusieurs années de constituer un véritable gisement de données provenant de tous les domaines de la santé. Ces données ont pour caractéristiques d’être très hétérogènes et d’être produites à différentes échelles et dans différents domaines. Leur réutilisation dans le cadre de la recherche clinique, de la santé publique ou encore de la prise en charge des patients implique de développer des approches adaptées reposant sur les méthodes issues de la science des données. L’objectif de cette thèse est d’évaluer au travers de trois cas d’usage, quels sont les enjeux actuels ainsi que la place des data sciences pour l’exploitation des données massives en santé. La démarche utilisée pour répondre à cet objectif consiste dans une première partie à exposer les caractéristiques des données massives en santé et les aspects techniques liés à leur réutilisation. La seconde partie expose les aspects organisationnels permettant l’exploitation et le partage des données massives en santé. La troisième partie décrit les grandes approches méthodologiques en science des données appliquées actuellement au domaine de la santé. Enfin, la quatrième partie illustre au travers de trois exemples l’apport de ces méthodes dans les champs suivant : la surveillance syndromique, la pharmacovigilance et la recherche clinique. Nous discutons enfin les limites et enjeux de la science des données dans le cadre de la réutilisation des données massives en santé. / The dematerialization of health data, which started several years ago, now generates na huge amount of data produced by all actors of health. These data have the characteristics of being very heterogeneous and of being produced at different scales and in different domains. Their reuse in the context of clinical research, public health or patient care involves developing appropriate approaches based on methods from data science. The aim of this thesis is to evaluate, through three use cases, what are the current issues as well as the place of data sciences regarding the reuse of massive health data. To meet this objective, the first section exposes the characteristics of health big data and the technical aspects related to their reuse. The second section presents the organizational aspects for the exploitation and sharing of health big data. The third section describes the main methodological approaches in data sciences currently applied in the field of health. Finally, the fourth section illustrates, through three use cases, the contribution of these methods in the following fields: syndromic surveillance, pharmacovigilance and clinical research. Finally, we discuss the limits and challenges of data science in the context of health big data.