Endometriosis is a heterogeneous chronic pain and inflammatory disease associated with negative impacts on quality of life. Among the phenotypes of endometriosis, deep endometriosis (DE) is the most aggressive form of the disease, associated with complex disease states, such as adhesions within the pouch of Douglas (POD) and bowel DE. The most common site of DE is the uterosacral ligaments (USLs), which are bilateral structures between the uterus and sacrum conjoined by the torus uterinus (TU), with a prevalence of 20 to 70%. The USLs have historically been the hardest to visualize using non-invasive modalities, such as transvaginal ultrasound (TVS), resulting in poor identification of endometriosis when present on/within the USLs, contributing to the significant diagnostic delay associated with the disease. This thesis details a novel diagnostic approach, utilizing TVS within the posterior vaginal fornix as the index test and laparoscopic visualization as the reference standard, aiming to evaluate the diagnostic accuracy of TVS for DE of the USLs and TU. Additionally, the USLs and TU are commonly associated with complex disease presentations, including POD obliteration and bowel DE, though the impact on diagnostic accuracy remains unknown. We theorize that these concurrent complex disease states will lead to the distortion of the anatomical environment and, in turn, negatively alter the diagnostic performance of the novel posterior approach. This thesis further aimed to determine the impact of concurrent complex disease states on diagnostic performance. We found enhanced diagnostic accuracy in the detection of endometriosis in the left USL, right USL, and TU compared to previous studies, with our sensitivity ranging from 75.0-100%, specificity of 100%, positive predictive values of 100%, and negative predictive value ranging from 88.6-100%. Furthermore, contrary to our hypothesis, diagnostic performance appeared unaffected by the presence of complex disease states. The ability to diagnose USL DE non-invasively can have profound implications for introducing personalized treatment plans in a timely manner, which should improve patient outcomes. With this enhanced diagnostic performance, fewer people will require a surgical diagnosis, which reduces the burden on the health system and decreases surgical complications associated with diagnostic surgery. / Thesis / Master of Science (MSc) / Endometriosis is a common gynecological disease involving the abnormal growth of uterine-like cells outside the uterus, causing significant negative impacts on quality of life and diagnostic delays. Deep endometriosis (DE) is the most aggressive form, infiltrating surrounding tissues and leading to complex disease states. The uterosacral ligaments (USLs; connective structures between the lower spine and uterus) are the most common site for DE, but diagnosing them non-invasively remains challenging, aiding the diagnostic delay. Following updated classification guidelines, the overarching aim of this thesis is to enhance our understanding of transvaginal ultrasound (TVS) as a safe and rapid diagnostic for DE of the USLs and TU. In doing so, this thesis aims to assess the accuracy of a new TVS technique for DE of the USLs and determine how other related health conditions might affect the accuracy of this diagnostic approach. The findings from this study indicate that using TVS could greatly assist in diagnosing DE in the USLs, potentially leading to more personalized treatment approaches by healthcare providers and better outcomes for individuals with endometriosis. In summary, this research contributes significantly to our understanding and management of this complex condition.

A diagnostic test identifies patients according to their disease status. Different meta-analytic models for diagnostic test accuracy studies have been developed to synthesize the sensitivity and specificity of the test. Because of the likely correlation between the sensitivity and specificity of a test, modeling the two parameters using a bivariate model is desirable. Historically, the logit transformation has been used to model sensitivity and specificity pairs from multiple studies as a bivariate normal. In this thesis, we propose two transformations, the arcsine square root and the Freeman-Tukey double arcsine transformation, in the context of a bivariate random-effects model to meta-analyze diagnostic test accuracy studies. We evaluated the performance of the three transformations (the commonly used logit and the proposed transformations) using an extensive simulation study in terms of bias, root mean square error and coverage probability. We illustrate the methods using three real data sets. The simulation study results showed that, for smaller sample size and higher values of sensitivity and specificity, the proposed transformations are less biased, have smaller root mean square error and better coverage probability than the standard logit transformation regardless of the number of studies. On the other hand, for large sample sizes, the usual logit transformation is less biased and has better coverage probability regardless of the true values of sensitivity, specificity and number of studies. However, when the sample size is large, the logit transformation has better root mean square error for moderate and large number of studies. The point estimates of the two parameters, sensitivity & specificity, from the methods using the three real data sets follow patterns similar to those reported by our simulation. / Thesis / Master of Science (MSc)

Meta-analysis is a popular statistical method that synthesizes evidence from multiple studies. Conventionally, both the hierarchical and bivariate models for meta-analysis of diagnostic test accuracy (DTA) studies assume that the random-effects follow the bivariate normal distribution. However, this assumption is restrictive, and inferences could be misleading when it is violated. On the other hand, subjective methods such as inspection of forest plots are used to identify outlying studies in a meta-analysis of DTA studies. Moreover, inferences made using the well-established bivariate random-effects models, when outlying or influential studies are present, may lead to misleading conclusions. Thus, the aim of this thesis is to address these issues by introducing alternative and robust statistical methods. First, we extend the current bivariate linear mixed model (LMM) by assuming a flexible bivariate skew-normal distribution for the random-effects. The marginal distribution of the proposed model is analytically derived so that parameter estimation can be performed using standard likelihood methods. Overall, the proposed model performs better in terms of confidence interval width of the overall sensitivity and specificity, and with regards to bias and root mean squared error of the between-study (co)variances than the traditional bivariate LMM. Second, we propose objective methods based on solid statistical reasoning for identifying outlying and/or influential studies in a meta-analysis of DTA studies. The performances of the proposed methods are evaluated using a simulation study. The proposed methods outperform and avoid the subjectivity of the currently used ad hoc approaches. Finally, we develop a new robust bivariate random-effects model which accommodates outlying and influential observations and leads to a robust statistical inference by down-weighting the effect of outlying and influential studies. The proposed model produces robust point estimates of sensitivity and specificity compared to the standard models, and also generates a similar point and interval estimates of sensitivity and specificity as the standard models in the absence of outlying or influential studies. / Thesis / Doctor of Philosophy (PhD) / Diagnostic tests vary from the noninvasive rapid strep test used to identify whether a patient has a bacterial sore throat to the much complex and invasive biopsy test used to examine the presence, cause, and extent of a severe condition, say cancer. Meta-analysis is a widely used statistical method that synthesizes evidence from several studies. In this thesis, we develop novel statistical methods extending the traditional methods for meta-analysis of diagnostic test accuracy studies. Our proposed methods address the issue of modelling asymmetrical data, identifying outlier studies, and optimally accommodating these outlying studies in a meta-analysis of diagnostic test accuracy studies. Using both real-life and simulated datasets, we show that our proposed methods perform better than conventional methods in a wide range of scenarios. %Therefore, we believe that our proposed methods are essential for methodologists, clinicians and health policy professionals in the process of making a correct judgment to using the appropriate diagnostic test to diagnose patients.

Background: The coronavirus disease 2019 (COVID-19) presents diagnostic evaluation and patient management challenges, including uncertainty regarding the role of imaging tests. This series of reviews from the suite of Cochrane ‘living systematic reviews’ aims to evaluate the accuracy of chest imaging (computed tomography (CT), X-ray and ultrasound) for diagnosis and management of individuals with suspected COVID-19. Methods: The Bern COVID-19 Living Database, Cochrane COVID-19 Register, and CDC Library were searched through 30 September 2020 (for review version 3) and 17 February 2021 (for review version 4). Diagnostic accuracy studies involving participants with suspected COVID-19 were included. Screening, data extraction, and risk of bias assessments (using the QUADAS-2 tool) were completed independently, in duplicate. Pooled accuracy estimates and 95% confidence intervals (CIs) were determined using a bivariate random effects model. Results: In the third version of the review, chest CT (41 studies, 16133 participants, 8110 (50%) cases) had a pooled sensitivity of 87.9% (95%CI 84.6-90.6) and specificity of 80.0% (74.9-84.3). Chest X-ray (9 studies, 3694 participants, 2111 (57%) cases) had a pooled sensitivity of 80.6% (69.1-88.6) and specificity of 71.5% (59.8-80.8). Ultrasound of the lungs (5 studies, 446 participants, 211 (47%) cases) had a pooled sensitivity of 86.4% (72.7-93.9) and specificity of 54.6% (35.3-72.6). Indirect comparisons showed that chest CT gave higher specificity (P=0.0052) and similar sensitivity (P=0.77) compared to ultrasound. There were no differences (P≥0.05) in accuracy between CT and X‐ray, or X‐ray and ultrasound. In the fourth version of the review, chest CT (69 studies, 28285 participants, 14342 (51%) cases) had a pooled sensitivity of 86.9% (83.6-89.6) and specificity of 78.3% (73.7-82.3). Chest X‐ray (17 studies, 8530 participants, 5303 (62%) cases) had a pooled of sensitivity=73.1% (64.1-80.5) and specificity of 73.3% (61.9-82.2). Ultrasound of the lungs (15 studies, 2410 participants, 1158 (48%) cases) had a pooled sensitivity of 88.9% (84.9-92.0) and specificity of 72.2% (58.8-82.5). Indirect comparisons showed that chest CT and ultrasound had similar sensitivities (P=0.42), and each gave higher sensitivities than X-ray (P=0.0003 and P=0.001, respectively). All modalities had similar specificities (P≥0.05). Conclusion: The most recent evidence indicates that both chest CT and ultrasound of the lungs are sensitive and moderately specific for diagnosing individuals with suspected COVID-19, while chest X-ray is moderately sensitive and moderately specific. Chest CT and ultrasound may be useful for ruling out COVID‐19, but not for distinguishing COVID-19 from other illnesses. Research assessing the prognostic value of imaging for predicting morbidity and mortality in individuals with COVID-19 is underway and will also be published in the suite of Cochrane ‘living' systematic reviews.

Systematic reviews on diagnostic test accuracy studies provide an overview of the current literature in a systematic and transparent manner. They are the highest level of evidence in clinical research, therefore they are critical to decision-making in the healthcare setting. Cancer is the primary source of mortality in Canada, however early detection of tumors can improve the survival rates and long-term health outcomes of patients. The primary method of cancer diagnosis is histopathological assessment, however, its use remains controversial. It is an invasive procedure and requires resources and clinical expertise not readily available. Noninvasive clinical imaging has been studied as a clinically desirable method for cancer diagnosis, however its diagnostic accuracy has yet to be established in the medical setting. With the increased role of DTA research in medicine, the current literature needs to be summarized in an effective way to properly educate and influence clinical decision-making. The objective of this thesis is to address the current evidence gaps in DTA research by conducting several systematic reviews to evaluate the accuracy of diagnostic methods in cancer-related imaging. The last chapter of the thesis will provide a critical reflection on the current landscape of DTA studies in cancer-related imaging, based on the findings of the reviews in the thesis.

[pt] Neuroticismo é um fator de personalidade que engloba quatro subfatores: depressão, vulnerabilidade, passividade e instabilidade emocional. Esta pesquisa teve como objetivos construir e buscar evidências de validade de medidas implícitas para aferir as facetas de neuroticismo. Para tanto, foram realizados dois estudos: (1) elaboração dos itens; (2) teste empírico das medidas. O primeiro estudo consistiu em um procedimento empírico para selecionar itens e buscar evidências de validade baseadas no conteúdo das medidas construídas. Participaram 408 pessoas, sendo que todas eram estudantes universitárias. Esse procedimento resultou em listas de palavras representativas do indivíduo e das facetas de neuroticismo. No segundo estudo, as palavras selecionadas previamente foram implementadas em testes de associação implícita para que fossem buscadas mais evidências de validade e obtidos indicadores de fidedignidade. Participaram 417 pessoas com diferentes níveis de escolaridade, sendo que 72,2 por cento tinham ensino superior incompleto e 61,4 por cento eram mulheres. Os resultados indicaram que as medidas de depressão, insegurança e passividade apresentaram evidências de validade satisfatórias, incluindo uma estrutura consonante com as definições dos construtos e relações esperadas com outras variáveis. Por exemplo, encontraram-se correlações positivas entre as medidas construídas e neuroticismo e correlações negativas com satisfação de vida. A medida de instabilidade emocional, por outro lado, se mostrou mais problemática no que diz respeito às evidências de validade. Ainda, os índices de consistência interna de todas as medidas se mostraram adequados e os coeficientes de correlação teste-reteste foram superiores aos valores que têm sido encontrados na literatura. Discute-se, entretanto, que mais evidências de validade são necessárias para que essas medidas possam ser usadas em contextos aplicados. / [en] Neuroticism is a personality factor that encompasses four subfactors: depression, vulnerability, passivity and emotional instability. This research aimed to build and search for evidence of validity of implicit measures to assess the facets of neuroticism. For this purpose, two studies were conducted: (1) elaboration of the items; (2) empirical test of the measures. The first study consisted of an empirical procedure to select items and search for evidence of validity based on the content of the built measures. Participants were 408 people, all of them were university students. This procedure resulted in lists of representative words of the individual and the facets of neuroticism. On the second study, the previously chosen words were implemented on implicit association tests, so that more evidence of validity was sought and reliability indicators were obtained. Participants were 417 people with different levels of educational background, 72.2 percent of them had incomplete higher educational background and 61.4 percent were women. The results indicated that the measures of depression, insecurity and passivity presented satisfactory evidence of validity, including a structure aligned with the definition of the constructs and expected relations to other variables. For instance, we found positive correlations between the built measures and neuroticism and negative correlations with satisfaction with life. The measure of emotional instability, however, proved to be more problematic regarding the evidence of validity. In addition, the internal consistency indexes for all measures were found to be adequate and the test-retest correlation coefficients were higher than the values found in previous studies. It is argued, however, that more evidence of validity is needed so that these measures can be used in applied contexts.

CONTEXTE La syphilis est une maladie ré-émergente depuis 2000. Son traitement est simple, mais son diagnostic est complexe. La technique d’amplification génique de Treponema pallidum (Tp-PCR) existe depuis 1990 mais le CDC l’a incluse dans sa définition de cas en janvier 2014. OBJECTIFS 1) Evaluer la performance diagnostique de la Tp-PCR à différents stades cliniques et milieux biologiques. 2) Mesurer la sensibilité, spécificité et les valeurs prédictives de la Tp-PCR en fonction de 3 groupes de référence dans des ulcères récents. 3) Comparer les performances des 2 principales cibles de Tp-PCR.MATÉRIEL ET MÉTHODES Premièrement, une revue systématique et méta-analyse des études publiées depuis 1990 ont été menées. Ensuite une étude multicentrique prospective a été conduite dans 5 villes européennes pendant 2 ans chez des patients avec un ulcère oro-génital. Tous ont reçu le test de référence local et 2 Tp-PCRs dans l’ulcère (gène tpp47 vs. polA). Les valeurs de sensibilité, spécificité et valeurs prédictives de la Tp-PCR ont été calculées comparativement au fond noir (FN), à la sérologie et à un gold standard amélioré. La concordance des 2 cibles a été évaluée par un coefficient kappa.RÉSULTATS PRINCIPAUX La méta-analyse conclut que la Tp-PCR a une meilleure performance dans les ulcères récents. L’étude clinique montre que la Tp-PCR décrit une meilleure performance comparativement au gold standard amélioré et a même une meilleure sensibilité que le FN. Les 2 cibles ont la même valeur diagnostique et une concordance quasi parfaite. CONCLUSIONS La Tp-PCR ciblant tpp47 ou polA est cliniquement utile pour diagnostiquer une syphilis primaire et pourrait même remplacer le FN sous certaines conditions. / BACKGROUND Syphilis has re-emerged in at-risk populations since 2000. Although the treatment of syphilis is simple, its diagnosis remains challenging. Treponema pallidum Polymerase Chain Reaction (Tp-PCR) has been used in the diagnosis of syphilis since 1990 but it is included in the case definition of the CDC since January 2014. OBJECTIVES 1) To assess the accuracy of Tp-PCR in various biological specimens and syphilis stages. 2) To measure its diagnostic performance (sensitivity, specificity and predictive values) in ulcers from early syphilis compared to three groups of reference. 3) To compare the accuracy of the two most currently used targets: tpp47 and polA genes.METHODS We conducted a systematic review and meta-analysis of all studies published from 1990. We implemented a multicentre, prospective, observational study in 5 European cities between 09/2011 and 09/2013 among patients with an oral or genital ulcer suggestive of syphilis. All patients were tested with traditional reference tests plus 2 Tp-PCRs (tpp47 and polA). We estimated the sensitivity, specificity and predictive values of Tp-PCR compared to darkfield microscopy (DFM), serology and an enhanced gold standard. We used the kappa coefficient to assess the agreement between the 2 targets.MAIN RESULTST p-PCR had the best accuracy in ulcers from early syphilis. Tp-PCR performed better when compared to the enhanced gold standard and had a higher sensitivity than DFM. The 2 Tp-PCRs had a similar accuracy and an almost perfect agreement.CONCLUSIONS Tp-PCR targeting either tpp47 or polA is clinically useful to confirm an early syphilis in smears and could even replace DFM under specific conditions.

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