京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第22311号 / 医博第4552号 / 新制||医||1040(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 福原 俊一, 教授 坂井 義治, 教授 妹尾 浩 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

Background and Significance: Narcolepsy is a chronic neurological disorder. These patients experience various psychiatric and physical comorbid diseases and mortality at an increased rate compared to the general population. Additionally, patients with narcolepsy experience approximately a doubling of various annual healthcare related facility visits, transactions, and costs comparatively. Narcolepsy with cataplexy is generally believed to be more prevalent than narcolepsy without cataplexy. However, incidence and prevalence estimates of narcolepsy (with or without cataplexy) vary widely with few large epidemiological studies conducted worldwide and none in the U.S evaluating these proportions in both children and adults utilizing a large health care claims database. One of the main mechanisms underlying narcolepsy, the destruction of hypocretin neurons, is not clear. Two of the more noted hypotheses for this pathology are autoimmune and infection based triggers in allele carrier patients. These have been highlighted since narcolepsy diagnoses increased following the late 2000s influenza vaccinations, especially across Europe. Specific influenza and streptococcal infections have also been considered. Large U.S. healthcare claims database investigations of the association between specific infections and development of narcolepsy were not found in the published scientific literature. Our goals were to enhance the knowledge regarding the epidemiology and possible infection triggers of narcolepsy. The information gained may aid in the overall understanding of the condition, the possible vulnerable populations, and lead to hypotheses regarding which subpopulations research should be focused upon and those triggers that may be avoided or reduced in exposure. Methods: The Truven Health MarketScan Commercial Dissertation Database (THMCDD) was used to estimate prevalence and incidence of narcolepsy, with and without cataplexy, by age groups, gender, and region among patients under age 66 with continuous enrollment for years 2008-2010. THMCDD contains health claims information for over 18 million people. Prevalence was expressed as cases/100,000 persons. Average annual incidence (using varying criteria for latency between the diagnostic tests, polysomnograph coupled with MSLT, and the diagnosis) was expressed as new cases/100,000 persons/year. Subsequently, we conducted a case-control study to assess the differences in respiratory infections between patients with incident narcolepsy diagnosis and controls. Continuously enrolled patients under age 66 were included. Cases of narcolepsy occurring from July 1, 2009 through December 31, 2010 were included based on two diagnosis criteria (using varying criteria for latency between diagnosis and the diagnostic tests). Non-narcolepsy controls were frequency matched on look-back time by assigning an index date equal to a case diagnosis date. Occurrence of prior respiratory infections was compared between cases and controls based on narcolepsy criteria and four different time periods pre-index date. Infections were grouped into 9 types based on pathogen and clinical manifestation. Results: From 2008 through 2010, there were 8,444,517 continuously enrolled patients and 6,703 diagnosed with narcolepsy (prevalence overall:79.4/100,000; without cataplexy:65.4/100,000; with cataplexy: 14.0/100,000). Based on the 3 definitions of incidence, overall average annual incidence was 7.67, 7.13, and 4.87/100,000 persons/year. Incidence for narcolepsy without cataplexy was generally several times higher than narcolepsy with cataplexy. Prevalence and incidence were approximately 50% greater for females compared to males across most age groups. Prevalence was highest among the 21-30 age group, with incidence highest among enrollees in their early 20s and late teens. Regionally, the North Central U.S. had the highest prevalence and incidence, while the West was the lowest. For the case-control study, Adjusted odds ratio (aOR) increases were statistically significant for Group 5 (acute respiratory infections), Group 8 (other pneumonias, bronchopneumonia, etc.) and Group 9 (influenzas) across various time periods pre-index date and for both narcolepsy criteria. Overall, the most significant aORs were for acute respiratory infections during the 3 to 15 months pre-index date for both narcolepsy diagnosis criteria (aOR=1.73, 95% 1.52 to 1.98 and aOR=1.83, 95% CI 1.57 to 2.19). The aORs for acute respiratory infections were approximately 50% greater among females than males. Conclusion: We observed higher prevalence and incidence of narcolepsy compared to most previous studies. Females were associated with approximately 50% increased proportions compared to males. We also found that the greatest prevalence and incidence of narcolepsy occurred in patients in their early 20s, and those residing in the North Central region of the U.S. Perhaps most striking was the observation of much greater proportions of narcolepsy without cataplexy compared to narcolepsy with cataplexy. In the case-control assessment, we found increased occurrences of acute respiratory infections, pneumonias, and influenza prior to incident narcolepsy diagnosis, compared to controls. Generally, these rates appeared higher for females than males and occurred for both narcolepsy diagnosis criteria. Additionally, these associations were observed in the infection assessment periods 3 to 15 months and 6 to 18 months prior to incident narcolepsy diagnosis. Increased awareness and early notification among healthcare providers for signs and symptoms of narcolepsy is critical in helping this population of patients manage this burdensome condition. Also, the identification of potential narcolepsy triggers by certain infections may aid in the understanding of the disease. These findings may have implications in the understanding of mechanisms and causation of other acute onset neurological disorders. Our observations of consistently increased risk of incident narcolepsy related to recent previous viral respiratory infections and the inconsistent results for bacterial infections require additional study to confirm these findings.

京都大学 / 新制・課程博士 / 博士(医学) / 甲第24970号 / 医博第5024号 / 新制||医||1069(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 中山 健夫, 教授 川上 浩司, 教授 大鶴 繁 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

No description available.

La fibrillation auriculaire (FA), l’arythmie cardiaque la plus courante est un facteur de risque majeur pour le développement de l’accident vasculaire cérébral ischémique (AVC). Les anticoagulants oraux directs (AOD) ont largement remplacé la warfarine en usage clinique pour la prévention des AVC dans la FA. Cette recherche a examiné deux défis méthodologiques importants qui peuvent survenir dans les études observationnelles sur l’efficacité et l’innocuité comparatives des AOD et de la warfarine. Premièrement : un biais d’information résultant d’une classification erronée de l’exposition au traitement à la warfarine suite aux ajustements de doses fréquentes qui ne sont pas adéquatement consignés dans les données de dispensations pharmacologiques. Deuxièmement : un biais de sélection, en raison de la censure informative, généré par des mécanismes de censure différentiels, chez les patients exposés aux AOD, ou à la warfarine. À l’aide des données administratives du Québec, j’ai mené trois études de cohortes rétrospectives qui ont portées sur toutes les personnes ayant initié un anticoagulant oral de 2010 à 2016. Ces études étaient restreintes aux résidents du Québec couverts par le régime public d'assurance médicaments (environ 40% de la population au Québec), c’est-à-dire : des personnes âgées de 65 ans et plus; des bénéficiaires de l’aide sociale; des personnes qui n’ont pas accès à une assurance-maladie privée; et les personnes à leur charge. Dans la première étude, nous avons émis l'hypothèse que les données sur les réclamations en pharmacie ne reflètent pas correctement la durée de la dispensation de la warfarine. Les écarts entre les renouvellements consécutifs étaient plus grands pour la warfarine que les AOD. Dans cette étude, on a trouvé que l'écart moyen pour les usagers de la warfarine était de 9.3 jours (avec un intervalle de confiance de 95% [IC]: 8.97-9.59), l'apixaban de 3.08 jours (IC de 95%: 2.96--3.20), et de 3.15 jours pour le rivaroxaban (IC de 95%: 3.03-3.27). Les écarts entre les renouvellements consécutifs présentaient une plus grande variabilité chez les personnes qui prenaient de la warfarine comparativement à celles qui prenaient des AOD. Cette variation peut refléter les changements de posologie de la warfarine lorsque la dose quotidienne est ajustée par le professionnel de la santé en fonction des résultats du rapport normalisé international (INR). L’ajustement de la dose peut prolonger (ou raccourcir) la période couverte par le nombre de comprimés délivrés. Dans la deuxième étude, nous avons émis l'hypothèse que la définition de la durée d'exposition basée sur la variable des « jours fournis », disponible dans la base de données, et le délai de grâce fixe, entraîneront une erreur de classification différentielle de l’exposition à la warfarine par rapport aux AOD. Dans cette étude, on a utilisé deux approches pour définir la durée des dispensations : la variable des « jours fournis » disponible dans la base de données ainsi qu’une approche axée sur les données pour la définition de la durée de dispensation qui tient compte des antécédents de distribution précédents. La deuxième étude a révélé qu'en utilisant la variable des « jours fournis », la durée moyenne (et l'écart type) des durées des dispensations pour le dabigatran, le rivaroxaban, et la warfarine étaient de 19 (15), 19 (14), et de 13 (12) jours, respectivement. En utilisant l’approche fondée sur des données, les durées étaient de 20 (16), 19 (15), et de 15 (16) jours, respectivement. Ainsi, l'approche fondée sur les données s’est rapprochée de la variable des « jours fournis » pour les thérapies à dose standard telles que le dabigatran et le rivaroxaban. Une approche axée sur les données pour la définition de la durée de dispensation, qui tient compte des antécédents de distribution précédents, permet de mieux saisir la variabilité de la durée de dispensation de la warfarine par rapport à la méthode basée sur la variable des « jours fournis ». Toutefois, cela n’a pas eu d’impact sur les estimations du rapport de risque sur la sécurité comparative des AOD par rapport à la warfarine. Dans la troisième étude, nous avons émis l'hypothèse que lors de l'évaluation de l’effet d’un traitement continu avec des anticoagulants oraux (l'analyse per-protocole), la censure élimine les patients les plus malades du groupe des AOD et des patients en meilleure santé du groupe de warfarine. Cela peut baisser l'estimation de l'efficacité et de l'innocuité comparative en faveur des AOD. L’étude a démontré que les mécanismes de censure chez les initiateurs d’AOD et de warfarine étaient différents. Ainsi, certaines covariables pronostiquement significatives, telles que l’insuffisance rénale chronique et l’insuffisance cardiaque congestive, étaient associées avec une augmentation de la probabilité de censure chez les initiateurs d’AOD, et une diminution de la probabilité de censure chez les initiateurs de warfarine. Pour corriger le biais de sélection introduit par la censure, nous avons appliqué la méthode de pondération par la probabilité inverse de censure. Deux stratégies de spécification du modèle pour l’estimation des poids de censure ont été explorées : le modèle non stratifié, et le modèle stratifié en fonction de l’exposition. L’étude a démontré que lorsque les poids de censure sont générés sans tenir compte des dynamiques de censure spécifiques, les estimés ponctuels sont biaisés de 15% en faveur des AOD par rapport à l'ajustement des estimés ponctuels avec des poids de censure stratifiée selon l’exposition (rapport de risque: 1.41; IC de 95%: 1.34, 1.48 et rapport de risque: 1.26; IC de 95%: 1.20, 1.33, respectivement). Dans l’ensemble, les résultats de cette thèse ont d’importantes implications méthodologiques pour les futures études pharmacoépidémiologiques. À la lumière de ceux-ci, les résultats des études observationnelles précédentes peuvent être revus et une certaine hétérogénéité peut être expliquée. Les résultats pourraient également être extrapolés à d’autres questions cliniques. / Atrial fibrillation (AF), the most common cardiac arrhythmia is a major risk factor for the development of ischemic stroke. Direct oral anticoagulants (DOACs) replaced warfarin in clinical use for stroke prevention in AF. This research investigated two important methodological challenges that may arise in observational studies on the comparative effectiveness and safety of DOACs and warfarin. First, an information bias resulting from misclassification of exposure to dose-varying warfarin therapy when using days supplied value recorded in pharmacy claims data. Second, a selection bias due to informative censoring with differential censoring mechanisms in the DOACs- and the warfarin exposure groups. Using the Québec administrative databases, I conducted three retrospective cohort studies that included patients initiating an oral anticoagulant between 2010 and 2016. The studies were restricted to Québec residents covered by the public drug insurance plan (about 40% of Québec’s population), including those aged 65 years and older, welfare recipients, those not covered by private medical insurance, and their dependents. In the first study, we hypothesized that pharmacy claims data inadequately captured the duration of the dispensation of warfarin. Gaps between subsequent dispensations (refill gaps) and their variation are larger for warfarin than for DOACs. In this study, we found that the average refill gap for the users of warfarin was 9.3 days (95% confidence interval [CI]:8.97-9.59), apixaban 3.08 days (95%CI: 2.96--3.20), dabigatran 3.70 days (95%CI: 3.56-3.84) and rivaroxaban 3.15 days (95%CI: 3.03-3.27). The variance of refill gaps was greater among warfarin users than among DOAC users. This variation may reflect the changes in warfarin posology when the daily dose is adjusted by a physician or a pharmacist based on previously observed international normalized ratio (INR) results. The dose adjustment may lead to a prolongation of the period covered by the number of dispensed pills. In the second study, we hypothesized that the definition of duration of dispensation based on the days supplied value and a fixed grace period will lead to differential misclassification of exposure to warfarin and DOACs. This may bias the estimate of comparative safety in favor of DOACs. In this study, we used two approaches to define the duration of dispensations: the recorded days supplied value, and the longitudinal coverage approximation (data-driven) that may account for individual variation in drug usage patterns. The second study found that using the days supplied, the mean (and standard deviation) dispensation durations for dabigatran, rivaroxaban, and warfarin were 19 (15), 19 (14), and 13 (12) days, respectively. Using the data-driven approach, the durations were 20 (16), 19 (15), and 15 (16) days, respectively. Thus, the data-driven approach closely approximated the recorded days supplied value for the standard dose therapies such as dabigatran and rivaroxaban. For warfarin, the data-driven approach captured more variability in the duration of dispensations compared to the days supplied value, which may better reflect the true drug-taking behavior of warfarin. However, this did not impact the hazard ratio estimates on the comparative safety of DOACs vs. warfarin. In the third study, we hypothesized that when assessing the effect of continuous treatment with oral anticoagulants (per-protocol effect), censoring removes sicker patients from the DOACs group and healthier patients from the warfarin group. This may bias the estimate of comparative effectiveness and safety in favor of DOACs. The study showed that the mechanisms of censoring in the DOAC and the warfarin exposure groups were different. Thus, prognostically meaningful covariates, such as chronic renal failure and congestive heart failure, had an opposite direction of association with the probability of censoring in the DOACs and warfarin groups. To correct the selection bias introduced by censoring, we applied the inverse probability of censoring weights. Two strategies for the specification of the model for the estimation of censoring weights were explored: exposure-unstratified and exposure-stratified. The study found that exposure-unstratified censoring weights did not account for the differential mechanism of censoring across the treatment group and failed to eliminate the selection bias. The hazard ratio associated with continuous treatment with warfarin versus DOACs adjusted with exposure unstratified censoring weights was 15% biased in favor of DOACs compared to the hazard ratio adjusted with exposure-stratified censoring weights (hazard ratio: 1.41; 95% CI: 1.34, 1.48 and hazard ratio: 1.26; 95%CI: 1.20, 1.33, respectively). Overall, the findings of this thesis have important methodological implications for future pharmacoepidemiologic studies. Moreover, the results of the previous observational studies can be reappraised, and some heterogeneity can be explained. The findings can be extrapolated to other clinical questions.