Advances in therapeutic risk management through signal detection and risk minimisation tool analyses

Les quatre principales activités de la gestion de risque thérapeutique comportent l’identification, l’évaluation, la minimisation, et la communication du risque. Ce mémoire aborde les problématiques liées à l’identification et à la minimisation du risque par la réalisation de deux études dont les objectifs sont de: 1) Développer et valider un outil de « data mining » pour la détection des signaux à partir des banques de données de soins de santé du Québec; 2) Effectuer une revue systématique afin de caractériser les interventions de minimisation de risque (IMR) ayant été implantées. L’outil de détection de signaux repose sur la méthode analytique du quotient séquentiel de probabilité (MaxSPRT) en utilisant des données de médicaments délivrés et de soins médicaux recueillis dans une cohorte rétrospective de 87 389 personnes âgées vivant à domicile et membres du régime d’assurance maladie du Québec entre les années 2000 et 2009. Quatre associations « médicament-événement indésirable (EI) » connues et deux contrôles « négatifs » ont été utilisés. La revue systématique a été faite à partir d’une revue de la littérature ainsi que des sites web de six principales agences réglementaires. La nature des RMIs ont été décrites et des lacunes de leur implémentation ont été soulevées. La méthode analytique a mené à la détection de signaux dans l'une des quatre combinaisons médicament-EI. Les principales contributions sont: a) Le premier outil de détection de signaux à partir des banques de données administratives canadiennes; b) Contributions méthodologiques par la prise en compte de l'effet de déplétion des sujets à risque et le contrôle pour l'état de santé du patient. La revue a identifié 119 IMRs dans la littérature et 1,112 IMRs dans les sites web des agences réglementaires. La revue a démontré qu’il existe une augmentation des IMRs depuis l’introduction des guides réglementaires en 2005 mais leur efficacité demeure peu démontrée.The four main components of therapeutic risk management (RM) consist of risk detection (identification), evaluation, minimisation, and communication. This thesis aims at addressing RM methodologies within the two realms of risk detection and risk minimisation, through the conduct of two distinct studies: i) The development and evaluation of a data mining tool to support signal detection using health care claims databases, and ii) A systematic review to characterise risk minimisation interventions (RMIs) implemented so far. The data mining tool is based on a Maximised Sequential Probability Ratio Test (MaxSPRT), using drug dispensing and medical claims data found in the Quebec health claims databases (RAMQ). It was developed and validated in a cohort of 87,389 community-dwelling elderly aged 66+, randomly sampled from all elderly drug plan members between 2000 and 2009. Four known drug-AE associations and two "negative" controls were used. The systematic review on RMIs is based on a literature search as well as a review of the websites of six main regulatory agencies. Types of RMIs have been summarized and implementation gaps identified. The data mining tool detected signals in one of four of the known drug-AE associations. Major contributions are: a) The first signal detection data mining tool applied to a Canadian claims database; b) Methodological improvements over published methods by considering the depletion of susceptibles effect and adjusting for overall health status to control for prescription channelling. The review yielded 119 distinct RMIs from the literature and 1,112 from the websites. The review demonstrated that an increase in RMI numbers among websites occurred since the introduction of guidances in 2005, but their effectiveness remains insufficiently examined

Pharmacoepidemiologic Studies: An Interrupted-time Series Analysis on Drug Utilization and Evalution of Beneficial or Adverse Drug Effects

Background: Pharmacoepidemiologic research is a valuable tool to enable one to understand medication utilization patterns, beneficial/harmful outcomes of drug therapy, and to evaluate the impact of other interventions on outcomes of drug therapy in “real-world” settings. Objectives: This dissertation aimed to apply pharmacoepidemiologic methods to examine (1) changes in utilization patterns of cholesterol-lowering medications following the release of the guidelines and evidence-based data, (2) the associations between statin use and gait speed decline in older adults, and (3) the associations between aspirin, non-aspirin nonsteroidal anti-inflammatory drugs or acetaminophen and risk of ovarian cancer. Methods: The study samples were from two sources including (1) community-dwelling older adults in the Health, Aging and Body Composition Study, and (2) 902 women with ovarian cancer and 1,802 controls in a population-based case-control study. An interrupted time-series analysis, multivariable generalized estimating equations, and multivariable logistic regression were used to examine our three objectives, respectively. Results: First, the use of cholesterol-lowering medication increased substantially over a decade in older adults, but was not related to a change in level or trend following the release of the evidence-based guidelines. Secondly, statin use had a decreased risk of gait speed decline. Thirdly, risk reductions of ovarian cancer were observed with the use of aspirin or selective COX-2 inhibitors. Conclusion: These findings suggest that further studies are needed to investigate risk-benefit balance of cholesterol-lowering therapy and the potential benefits/barriers of the treatment among adults aged ≥ 80 years. Moreover, further investigations are warranted to confirm the risk-benefit balance of statin use and physical function decline in older adults. Future research on the associations between aspirin use and the risk of ovarian cancer should better characterize accompanying medical conditions, health and lifestyle behaviors, genetic susceptibility, and the overall risk-benefit balance. The public health relevance of these findings is that understanding the utilization patterns of cholesterol-lowering therapy and potential benefits of statins on physical function may prevent cardiovascular disease and disability in older adults. In addition, aspirin or COX-2 inhibitors may be potential agents for the prevention of ovarian cancer, the second leading gynecologic cancer in the US

Self-reported health care utilization: measurement issues, data validity and implications for design of health surveys and economic evaluations An empirical investigation among patients with diabetes mellitus

Objectives: 1. To develop, test and refine a questionnaire collecting data on health care utilization in patients with diabetes. 2. To develop methods for a validation study quantifying the accuracy of self-reported health care utilization data. Methods: The questionnaire on health care utilization was developed and tested by a combination of behavior coding and cognitive interviews in 43 patients with diabetes mellitus types 1 and 2 in Germany. Theoretical considerations and empirical evidence with regard to validity of self-reported health care utilization were reviewed. Results: The questionnaire on health care utilization for use in diabetes research in Germany was developed and refined after careful testing. Only few studies investigated how to improve accuracy of self-reported health care utilization. To this end, it was decided to validate the questionnaire for two different recall periods applying an experimental design. Conclusion: More experimental studies, i.e. randomized allocation of participants to different questionnaire modes, recall periods, etc. are needed to better quantify the benefits of various data collection methods

Applications of big knowledge summarization

Advanced technologies have resulted in the generation of large amounts of data ( Big Data ). The Big Knowledge derived from Big Data could be beyond humans\u27 ability of comprehension, which will limit the effective and innovative use of Big Knowledge repository. Biomedical ontologies, which play important roles in biomedical information systems, constitute one kind of Big Knowledge repository. Biomedical ontologies typically consist of domain knowledge assertions expressed by the semantic connections between tens of thousands of concepts. Without some high-level visual representation of Big Knowledge in biomedical ontologies, humans cannot grasp the big picture of those ontologies. Such Big Knowledge orientation is required for the proper maintenance of ontologies and their effective use. This dissertation is addressing the Big Knowledge challenge - How to enable humans to use Big Knowledge correctly and effectively (referred to as the Big Knowledge to Use (BK2U) problem) - with a focus on biomedical ontologies. In previous work, Abstraction Networks (AbNs) have been demonstrated successful for the summarization, visualization and quality assurance (QA) of biomedical ontologies. Based on the previous research, this dissertation introduces new AbNs of various granularities for Big Knowledge summarization and extends the applications of AbNs. This dissertation consists of three main parts. The first part introduces two advanced AbNs. One is the weighted aggregate partial-area taxonomy with a parameter to flexibly control the summarization granularity. The second is the Ingredient Abstraction Network (IAbN) for the National Drug File - Reference Terminology (NDF-RT) Chemical Ingredients hierarchy, for which the previously developed AbNs for hierarchies with outgoing relationships, are not applicable. Since NDF-RT\u27s Chemical Ingredients hierarchy has no outgoing relationships. The second part describes applications of the two advanced AbNs. A study utilizing the weighted aggregate partial-area taxonomy for the identification of major topics in SNOMED CT\u27s Specimen hierarchy is reported. A multi-layer interactive visualization system of required granularity for ontology comprehension, based on the weighted aggregate partial-area taxonomy, is demonstrated to comprehend the Neoplasm subhierarchy of National Cancer Institute thesaurus (NCIt). The IAbN is applied for drug-drug interaction (DDI) discovery. The third part reports eight family-based QA studies on NCIt\u27s Neoplasm, Gene, and Biological Process hierarchies, SNOMED CT\u27s Infectious disease hierarchy, the Chemical Entities of Biological Interest ontology, and the Chemical Ingredients hierarchy in NDF-RT. There is no one-size-fits-all QA method and it is impossible to find a QA method for each individual ontology. Hence, family-based QA is an effective way, i.e., one QA technique could be applicable to a whole family of structurally similar ontologies. The results of these studies demonstrate that complex concepts and uncommonly modeled concepts are more likely to have errors. Furthermore, the three studies on overlapping concepts in partial-area taxonomies reported in this dissertation combined with previous three studies prove the success of overlapping concepts as a QA methodology for a whole family of 76 similar ontologies in BioPortal

Sodium-Glucose Cotransporter-2 Inhibitor Use and the Risk of Acute Kidney Injury in Older Adults in Routine Clinical Practice: A Population-Based Cohort Study

Regulatory agencies warn about acute kidney injury (AKI) risk following sodium-glucose cotransporter-2 (SGLT2) inhibitor use. This population-based retrospective cohort study in Ontario, Canada quantified the 90-day AKI risk in older adults who were newly dispensed either SGLT2 inhibitors or dipeptidyl peptidase-4 (DPP4) inhibitors in an outpatient setting between 2015 and 2017. Risk ratios (RR) were obtained using modified Poisson regression and risk differences using binomial regression. Relative to new use of a DPP4 inhibitor, initiation of an SGLT2 inhibitor was associated with a lower 90-day risk of a hospital encounter with AKI: 216 events in 19,611 patients (1.10%) versus 388 events in 19,483 patients (1.99%); weighted RR 0.79 (95% confidence interval 0.64–0.98). In routine care of older adults, new SGLT2 inhibitor use was associated with lower risk of AKI. Together with previous evidence, these findings suggest that regulatory warnings about AKI risk with SGLT2 inhibitors may be unwarranted

The Comparative Effectiveness of Trimodal Therapy Versus Definitive Chemoradiation in Older Adults with Locally Advanced Esophageal Cancer

Esophageal cancer has a poor prognosis. For locally advanced tumors, neoadjuvant chemoradiation followed by esophagectomy (trimodal therapy) and definitive chemoradiation are both endorsed by clinical practice guidelines. The existing evidence describing the use and comparative effectiveness of these therapies in older adults is out-of-date and impacted by strong bias. To address these limitations, our aims were to, in a population of older adults with locally advanced esophageal cancer, (1) describe temporal trends in, and factors related to, treatment receipt and (2) assess the comparative effectiveness and harms of trimodal therapy compared to definitive chemoradiation. We conducted two cohort studies using the Surveillance Epidemiology and End Results (SEER) cancer registry linked with Medicare administrative claims. In the first study, we found that the use of trimodal therapy increased from 2004 to 2017 for adenocarcinomas (annual percent change = 8.2; 95% CI: 4.8 – 11.7) and was stable for squamous cell carcinomas (annual percent change = 0.4; 95% CI: -4.1 – 5.1). Definitive chemoradiation increased during this time and became the dominant treatment strategy. Use of trimodal therapy decreased with increasing age, comorbidity burden, and frailty across both histologic subtypes. Use of carboplatin-based chemoradiation regimens increased over time, largely replacing cisplatin-based regimens. In the second study, we found that trimodal therapy decreased the risk of five-year overall mortality for adenocarcinomas (Risk Ratio (RR) = 0.88; 95% CI: 0.82 – 0.95) and squamous cell carcinomas (RR= 0.87; 95% CI: 0.70 – 1.01). Similar effect estimates were seen for cancer-specific mortality. However, trimodal therapy was found to increase the one-year cumulative incidence of functional adverse events for adenocarcinomas (RR= 1.40; 95% CI: 1.22 – 1.65) and squamous cell carcinomas (RR= 1.21; 95% CI: 1.00 – 1.49). Trimodal therapy was associated with about 165 added healthy days at home over a five-year span compared to definitive chemoradiation. In conclusion, the majority of older adults with locally advanced esophageal cancer receive definitive chemoradiation. Trimodal therapy is associated with longer survival, but the benefits are smaller than prior studies suggest. Given this benefit-risk profile and patient preferences, definitive chemoradiation may be appropriate for many in this population.Doctor of Philosoph

The Role of Signal Detection in Pharmacovigilance

The World Health Organisation defines pharmacovigilance as the science and activities relating to the detection, assessment, understanding and prevention of adverse effects or any other possible drug-related problems. Signal detection is a core pharmacovigilance activity. The motivation behind exploring signal detection and evaluation process is the timely detection of safety issues, and ultimately a better protection of public health. This thesis aimed to explore the processes of signal detection and evaluation and to inform regulatory decision making by providing evidence-based solutions to some of the existing questions. We investigated methods of detection and alternative data sources. Furthermore, we were interested to find out which characteristics of drugs make them more prone to have safety issues discovered post-marketing and tried to find predictive characteristics and we tried to gain some insight in the prioritisation process. The current work is relevant for all involved stakeholders, as European Medicines Agency (EMA), national regulatory authorities, pharmaceutical industry and, healthcare professionals and researchers

The Fracture – Mortality Association and The Effect of Osteoporosis Treatment on Mortality: A Multinational Study

Fractures, the main consequences of osteoporosis, are associated with subsequent fractures and mortality. However, limited evidence exists on the impact of non-hip non-vertebral (NHNV) fractures and subsequent fractures on mortality in ageing populations. Bisphosphonates (BPs), the most used osteoporosis treatment, have been associated with reduced mortality. Denosumab (Dmab), an increasingly prescribed osteoporosis treatment, is effective at reducing fractures, but unlike BPs, its effect on mortality has not been well-explored. Moreover, the safety of BPs is unclear in patients with moderate-severe chronic kidney disease (CKD) who have a high risk of fracture and are usually excluded from drug trials. Therefore, using data from Norway, UK, Spain and Australia, this thesis explores the impact of osteoporotic fracture types and subsequent fractures on mortality. It also examines the association between BPs and Dmab and mortality and investigates the effect of BPs on mortality in patients with moderate-severe (Grade 3B-5D) chronic kidney disease (CKD). Norway has one of the highest fracture rates in the world. Using data from the Tromsø Study, Norway, this research demonstrated two-fold increased mortality following hip fractures, and proximal NHNV fractures were associated with an increased mortality risk of 49% in women and 81% in men. A subsequent fracture following any initial fracture increased mortality risk by 89% in women and 77% in men. The Sax Institute’s 45 and Up Study, NSW, Australia, demonstrated that oBPs in both genders and Dmab in women were associated with 44% and 48% reduced mortality risk post-fracture, respectively. Furthermore, data from the UK and Spain demonstrated that oral BPs (oBPs) were not associated with increased mortality among patients with moderate-severe CKD. Instead, oBPs in the UK cohort were associated with a decreased risk of mortality by 8% in the whole cohort, 11% in women, 20% in those with prior history of fracture, and 30% in those with CKD Grade 4-5D. In summary, this thesis confirmed the high mortality risk associated with different osteoporotic fractures and subsequent fractures, highlighting the need for personalised risk assessment post-fracture. It demonstrated that antiresorptive treatment improves survival in the general population, and oBPs are generally safe in moderate-severe CKD