A Canadian Simulation Model for Major Depressive Disorder: Study Protocol.

BACKGROUND: Major depressive disorder (MDD) is a common, often recurrent condition and a significant driver of healthcare costs. People with MDD often receive pharmacological therapy as the first-line treatment, but the majority of people require more than one medication trial to find one that relieves symptoms without causing intolerable side effects. There is an acute need for more effective interventions to improve patients' remission and quality of life and reduce the condition's economic burden on the healthcare system. Pharmacogenomic (PGx) testing could deliver these objectives, using genomic information to guide prescribing decisions. With an already complex and multifaceted care pathway for MDD, future evaluations of new treatment options require a flexible analytic infrastructure encompassing the entire care pathway. Individual-level simulation models are ideally suited for this purpose. We sought to develop an economic simulation model to assess the effectiveness and cost effectiveness of PGx testing for individuals with major depression. Additionally, the model serves as an analytic infrastructure, simulating the entire patient pathway for those with MDD. METHODS AND ANALYSIS: Key stakeholders, including patient partners, clinical experts, researchers, and modelers, designed and developed a discrete-time microsimulation model of the clinical pathways of adults with MDD in British Columbia (BC), including all publicly-funded treatment options and multiple treatment steps. The Simulation Model of Major Depression (SiMMDep) was coded with a modular approach to enhance flexibility. The model was populated using multiple original data analyses conducted with BC administrative data, a systematic review, and an expert panel. The model accommodates newly diagnosed and prevalent adult patients with MDD in BC, with and without PGx-guided treatment. SiMMDep comprises over 1500 parameters in eight modules: entry cohort, demographics, disease progression, treatment, adverse events, hospitalization, costs and quality-adjusted life-years (payoff), and mortality. The model predicts health outcomes and estimates costs from a health system perspective. In addition, the model can incorporate interactive decision nodes to address different implementation strategies for PGx testing (or other interventions) along the clinical pathway. We conducted various forms of model validation (face, internal, and cross-validity) to ensure the correct functioning and expected results of SiMMDep. CONCLUSION: SiMMDep is Canada's first medication-specific, discrete-time microsimulation model for the treatment of MDD. With patient partner collaboration guiding its development, it incorporates realistic care journeys. SiMMDep synthesizes existing information and incorporates provincially-specific data to predict the benefits and costs associated with PGx testing. These predictions estimate the effectiveness, cost-effectiveness, resource utilization, and health gains of PGx testing compared with the current standard of care. However, the flexible analytic infrastructure can be adapted to support other policy questions and facilitate the rapid synthesis of new data for a broader search for efficiency improvements in the clinical field of depression.

Cost-effectiveness of pharmacogenomic-guided treatment for major depression.

BACKGROUND: Pharmacogenomic testing to identify variations in genes that influence metabolism of antidepressant medications can enhance efficacy and reduce adverse effects of pharmacotherapy for major depressive disorder. We sought to establish the cost-effectiveness of implementing pharmacogenomic testing to guide prescription of antidepressants. METHODS: We developed a discrete-time microsimulation model of care pathways for major depressive disorder in British Columbia, Canada, to evaluate the effectiveness and cost-effectiveness of pharmacogenomic testing from the public payer's perspective over 20 years. The model included unique patient characteristics (e.g., metabolizer phenotypes) and used estimates derived from systematic reviews, analyses of administrative data (2015-2020) and expert judgment. We estimated incremental costs, life-years and quality-adjusted life-years (QALYs) for a representative cohort of patients with major depressive disorder in BC. RESULTS: Pharmacogenomic testing, if implemented in BC for adult patients with moderate-severe major depressive disorder, was predicted to save the health system $956 million ($4926 per patient) and bring health gains of 0.064 life-years and 0.381 QALYs per patient (12 436 life-years and 74 023 QALYs overall over 20 yr). These savings were mainly driven by slowing or avoiding the transition to refractory (treatment-resistant) depression. Pharmacogenomic-guided care was associated with 37% fewer patients with refractory depression over 20 years. Sensitivity analyses estimated that costs of pharmacogenomic testing would be offset within about 2 years of implementation. INTERPRETATION: Pharmacogenomic testing to guide antidepressant use was estimated to yield population health gains while substantially reducing health system costs. These findings suggest that pharmacogenomic testing offers health systems an opportunity for a major value-promoting investment.

Characterizing primary care patients with posttraumatic stress disorder using electronic medical records: a retrospective cross-sectional study.

BACKGROUND: Posttraumatic stress disorder (PTSD) has significant morbidity and economic costs. This study describes the prevalence and characteristics of patients with PTSD using primary care electronic medical record (EMR) data. METHODS: This retrospective cross-sectional study used EMR data from the Canadian Primary Care Sentinel Surveillance Network (CPCSSN). This study included 1,574 primary care providers located in 7 Canadian provinces. There were 689,301 patients that visited a CPCSSN provider between 1 January 2017 and 31 December 2019. We describe associations between PTSD and patient characteristics using descriptive statistics, chi-square, and multiple logistic regression models. RESULTS: Among the 689,301 patients included, 8,817 (1.3%, 95% CI 1.2-1.3) had a diagnosis of PTSD. On multiple logistic regression analysis, patients with depression (OR 4.4, 95% CI 4.2-4.7, P < 0.001), alcohol abuse/dependence (OR 1.7, 95% CI 1.6-1.9, P < 0.001), and/or drug abuse/dependence (OR 2.6, 95% CI 2.5-2.8, P < 0.001) had significantly higher odds of PTSD compared with patients without those conditions. Patients residing in community areas considered the most material deprived (OR 2.1, 95% CI 1.5-2.1, P < 0.001) or the most socially deprived (OR 2.8, 95% CI 2.7-5.3, P < 0.001) had higher odds of being diagnosed with PTSD compared with patients in the least deprived areas. CONCLUSIONS: The prevalence of PTSD in Canadian primary care is 1.3% (95% CI 1.25-1.31). Using EMR records we confirmed the co-occurrence of PTSD with other mental health conditions within primary care settings suggesting benefit for improved screening and evidence-based resources to manage PTSD.

Posttraumatic stress disorder (PTSD) is a mental health disorder with symptoms presenting after having experienced or witnessed a traumatic event. PTSD symptoms continue for more than 1 month after the event and negatively impact the health and social wellbeing of an individual. Primary care, including family doctors, nurse practitioners, and community paediatricians, are often the first point of healthcare for an individual. This study found that PTSD is diagnosed and managed in primary care. Patients with PTSD had comorbidities, substance use, and visited their primary care provider more frequently. Additionally, patients with PTSD often live in a community area that is experiencing high material and social deprivation. The presence of PTSD in primary care suggests the need for new and additional evidence-based resources to assist in managing this complex condition.

Magic Pools: Parallel Assessment of Transposon Delivery Vectors in Bacteria.

Transposon mutagenesis coupled to next-generation sequencing (TnSeq) is a powerful approach for discovering the functions of bacterial genes. However, the development of a suitable TnSeq strategy for a given bacterium can be costly and time-consuming. To meet this challenge, we describe a part-based strategy for constructing libraries of hundreds of transposon delivery vectors, which we term "magic pools." Within a magic pool, each transposon vector has a different combination of upstream sequences (promoters and ribosome binding sites) and antibiotic resistance markers as well as a random DNA barcode sequence, which allows the tracking of each vector during mutagenesis experiments. To identify an efficient vector for a given bacterium, we mutagenize it with a magic pool and sequence the resulting insertions; we then use this efficient vector to generate a large mutant library. We used the magic pool strategy to construct transposon mutant libraries in five genera of bacteria, including three genera of the phylum Bacteroidetes. IMPORTANCE Molecular genetics is indispensable for interrogating the physiology of bacteria. However, the development of a functional genetic system for any given bacterium can be time-consuming. Here, we present a streamlined approach for identifying an effective transposon mutagenesis system for a new bacterium. Our strategy first involves the construction of hundreds of different transposon vector variants, which we term a "magic pool." The efficacy of each vector in a magic pool is monitored in parallel using a unique DNA barcode that is introduced into each vector design. Using archived DNA "parts," we next reassemble an effective vector for making a whole-genome transposon mutant library that is suitable for large-scale interrogation of gene function using competitive growth assays. Here, we demonstrate the utility of the magic pool system to make mutant libraries in five genera of bacteria.

A Comparison of the Costs and Benefits of Bacterial Gene Expression.

To study how a bacterium allocates its resources, we compared the costs and benefits of most (86%) of the proteins in Escherichia coli K-12 during growth in minimal glucose medium. The cost or investment in each protein was estimated from ribosomal profiling data, and the benefit of each protein was measured by assaying a library of transposon mutants. We found that proteins that are important for fitness are usually highly expressed, and 95% of these proteins are expressed at above 13 parts per million (ppm). Conversely, proteins that do not measurably benefit the host (with a benefit of less than 5% per generation) tend to be weakly expressed, with a median expression of 13 ppm. In aggregate, genes with no detectable benefit account for 31% of protein production, or about 22% if we correct for genetic redundancy. Although some of the apparently unnecessary expression could have subtle benefits in minimal glucose medium, the majority of the burden is due to genes that are important in other conditions. We propose that at least 13% of the cell's protein is "on standby" in case conditions change.

Circle of care modelling: an approach to assist in reasoning about healthcare change using a patient-centric system.

BACKGROUND: Many health system and health Information and Communication Technology (ICT) projects do not achieve their expected benefits. This paper presents an approach to exploring changes in the healthcare system to better understand the expected improvements and other changes by using a patient-centric modelling approach. Circle of care modeling (CCM) was designed to assist stakeholders in considering healthcare system changes using a patient centric approach. METHODS: The CCM approach is described. It includes four steps, based on soft systems methodology: finding out, conceptual modelling, structured discussion, and describing potential improvements. There are four visualizations that are used though this process: patient-persona based rich pictures of care flows (as part of finding out), and three models: provider view, communication view, and information repository view (as part of conceptual modelling). RESULTS: Three case studies are presented where CCM was applied to different real-world healthcare problems: 1. Seeking improvements in continuity of care for end of life patients. 2. Exploring current practices for medication communication for ambulatory patients prior to an update of a jurisdictional drug information system. 3. Deciding how to improve attachment of patients to primary care. The cases illustrate how CCM helped stakeholders reason from a patient centered approach about gaps and improvements in care such as: data fragmentation (in 1), coordination efforts of medication management (in 2), and deciding to support a community health centre for unattached patients (in 3). DISCUSSION: The circle of care modelling approach has proved to be a useful tool in assisting stakeholders explore health system change in a patient centric approach. It is one way to instantiate the important principle of being patient centered into practice when considering health system changes.

From principles to practice: Description of a novel equity-based HCV primary care treatment model for PWID.

BACKGROUND: Knowledge is increasing regarding effective models of HCV care for people who inject drugs (PWID). However, examples implementing such models in primary care are lacking, leaving a gap in our applied understanding of how practically we best scale-up such care: this is critical and urgent if the benefits of treatment advances are to be realized for PWID. A CASE STUDY: The Cool Aid Community Health Centre (CHC) provides HCV programming for PWID, putting recent advances into practice. A case study of the CHC's HCV programming describes the practice experience and outcomes of its novel, multidisciplinary, primary care, inner-city HCV treatment program for PWID. This paper describes how this model of care functions to address the many barriers to treatment and successfully facilitate adherence to treatment. CONCLUSION: Medical advances for HCV will be ineffectual without effective management of complex barriers to care related to substance use, mental health, trauma, poverty, homelessness, criminalization, cultural issues, stigma and marginalization. HCV treatment for PWIDs benefits from low-threshold settings which are culturally appropriate and where trusting relationships between clients and providers are nurtured. Public investment in primary care treatment for PWID living with HCV, including investments in supports that address the social barriers faced by these vulnerable populations would build on existing evidence and improve HCV outcomes for PWID.

SmartMed: A Medication Management System to Improve Adherence.

Adherence is the degree to which patients comply with their caregivers prescribed treatments. Lack of adherence due to various causes negatively affects health objectives. Prior work in the field of medication management has indicated the usefulness of IT as a possible aid for those who have difficulty adhering to prescribed medication regimes. In this paper we present a medication management system (SmartMed) that has been designed to monitor and increase adherence. The SmartMed system consists of a portable pill bottle device, a local base station, and a cloud data service. It reminds users when it is time to take their medications, and acquires adherence data which is accessible for applications that query the data service. The project was undertaken as an undergraduate engineering design project. This paper describes the design and prototype implementation of this system and provides direction for future work.

Screening for lifestyle and mental health risk factors in the waiting room: feasibility study of the Case-finding Health Assessment Tool.

OBJECTIVE: To assess the feasibility and acceptability of administering the validated Case-finding Health Assessment Tool (CHAT) in Canadian family practice waiting rooms to identify risk factors for depression, anxiety, anger control,smoking, drinking, other drug use, gambling, exposure to abuse, and physical inactivity. DESIGN: Cross-sectional survey. SETTING: One urban academic family practice and one inner-city community health centre in British Columbia. PARTICIPANTS: Convenience sample of consecutive adult patients (19 years of age or older) and their attending family physicians. MAIN OUTCOME MEASURES: Rates of completion; positive responses to and wanting help with identified lifestyle and mental health risk factors; rates of objections to any questions; and positive and negative comments about the CHAT by participating physicians and patients. RESULTS: A total of 265 eligible adults presented in the waiting rooms over 5 full days and 3 half-days, 176 (66%) of whom enrolled in the study; 161(91%) completed the CHAT, and 107 (66%) completed acceptability feedback forms. The prevalence of risk factors among patients in the academic and inner-city practice samples was different, with 20% and 63%, respectively,recording positive responses to both depression screening questions,34% and 60% positive for anxiety, 11% and 71% currently smoking, 6%and 22% feeling they needed to cut down on alcohol, 1% and 48% having used recreational drugs in the past year, and 11% and 65% with problems controlling anger. While many requested help with reducing risk factors,such as smoking (20%) and mental health symptoms (25% to 27%), a total of 35% (57 of 161) wanted help with an identified issue that day. Patients and physicians found the CHAT acceptable, with no patients objecting to any question except the alcohol question (2 objected). Most comments were positive. CONCLUSION: The CHAT allowed efficient identification of 9 risk factors, as well as identification of those wanting help. It could be used to screen all or targeted adult Canadian primary care patients in waiting rooms.