Use of the instrumental inequalities in simulated mendelian randomization analyses with coarsened exposures.

Mendelian randomization (MR) requires strong unverifiable assumptions to estimate causal effects. However, for categorical exposures, the MR assumptions can be falsified using a method known as the instrumental inequalities. To apply the instrumental inequalities to a continuous exposure, investigators must coarsen the exposure, a process which can itself violate the MR conditions. Violations of the instrumental inequalities for an MR model with a coarsened exposure might therefore reflect the effect of coarsening rather than other sources of bias. We aim to evaluate how exposure coarsening affects the ability of the instrumental inequalities to detect bias in MR models with multiple proposed instruments under various causal structures. To do so, we simulated data mirroring existing studies of the effect of alcohol consumption on cardiovascular disease under a variety of exposure-outcome effects in which the MR assumptions were met for a continuous exposure. We categorized the exposure based on subject matter knowledge or the observed data distribution and applied the instrumental inequalities to MR models for the effects of the coarsened exposure. In simulations of multiple binary instruments, the instrumental inequalities did not detect bias under any magnitude of exposure outcome effect when the exposure was coarsened into more than 2 categories. However, in simulations of both single and multiple proposed instruments, the instrumental inequalities were violated in some scenarios when the exposure was dichotomized. The results of these simulations suggest that the instrumental inequalities are largely insensitive to bias due to exposure coarsening with greater than 2 categories, and could be used with coarsened exposures to evaluate the required assumptions in applied MR studies, even when the underlying exposure is truly continuous.

An evaluation of the cost-effectiveness of population genetic screening for familial hypercholesterolemia in US patients.

BACKGROUND AND AIMS: Familial hypercholesterolemia is an underdiagnosed genetic metabolic condition limiting the clearance of low-density lipoprotein cholesterol and increasing lifetime risk of cardiovascular disease. Population genetic screening in unselected individuals could quickly identify cases of familial hypercholesterolemia and enable early prevention, but the economic impact of widespread screening on patients has not been studied. METHODS: We assessed the cost-effectiveness of population genetic screening for familial hypercholesterolemia in 20 and 35-year-old adults in the United States from the perspective of patients. We developed a decision tree Markov hybrid model to examine diagnoses, cardiovascular disease, cardiac events, quality of life, and costs under population genetic screening compared to family-based cascade testing. RESULTS: While population genetic screening increased diagnoses and reduced incidence of cardiovascular disease, population genetic screening was not cost-effective compared to cascade testing at current levels of willingness to pay. Lower genetic testing costs, combined screening with other genetic conditions, and support to maintain lipid-lowering therapy use over time could improve the cost-effectiveness of population genetic screening. CONCLUSIONS: Future research is needed to examine how cost-sharing strategies may affect the cost-effectiveness of screening to patients and how families and providers experience the clinical and economic outcomes of population screening.

Using Polygenic Risk Scores for Prioritizing Individuals at Greatest Need of a Cardiovascular Disease Risk Assessment.

Background The aim of this study was to provide quantitative evidence of the use of polygenic risk scores for systematically identifying individuals for invitation for full formal cardiovascular disease (CVD) risk assessment. Methods and Results A total of 108 685 participants aged 40 to 69 years, with measured biomarkers, linked primary care records, and genetic data in UK Biobank were used for model derivation and population health modeling. Prioritization tools using age, polygenic risk scores for coronary artery disease and stroke, and conventional risk factors for CVD available within longitudinal primary care records were derived using sex-specific Cox models. We modeled the implications of initiating guideline-recommended statin therapy after prioritizing individuals for invitation to a formal CVD risk assessment. If primary care records were used to prioritize individuals for formal risk assessment using age- and sex-specific thresholds corresponding to 5% false-negative rates, then the numbers of men and women needed to be screened to prevent 1 CVD event are 149 and 280, respectively. In contrast, adding polygenic risk scores to both prioritization and formal assessments, and selecting thresholds to capture the same number of events, resulted in a number needed to screen of 116 for men and 180 for women. Conclusions Using both polygenic risk scores and primary care records to prioritize individuals at highest risk of a CVD event for a formal CVD risk assessment can efficiently prioritize those who need interventions the most than using primary care records alone. This could lead to better allocation of resources by reducing the number of risk assessments in primary care while still preventing the same number of CVD events.

Introducing and Implementing Genetic Assessment in Cardio-Obstetrics Clinical Practice: Clinical and Genetic Workup of Patients with Cardiomyopathy.

Cardiovascular disease (CVD) during pregnancy varies significantly worldwide, influenced by factors such as access to healthcare, delayed diagnosis, causes, and risk factors. Our study sought to explore the spectrum of CVD present in pregnant women in the United Arab Emirates to better understand this population's unique needs and challenges. Central to our study is an emphasis on the importance of implementing a multidisciplinary approach that involves the collaboration of obstetricians, cardiologists, geneticists, and other healthcare professionals to ensure that patients receive comprehensive and coordinated care. This approach can also help identify high-risk patients and implement preventive measures to reduce the occurrence of adverse maternal outcomes. Furthermore, increasing awareness among women about the risk of CVD during pregnancy and obtaining detailed family histories can help in the early identification and management of these conditions. Genetic testing and family screening can also aid in identifying inherited CVD that can be passed down through families. To illustrate the significance of such an approach, we provide a comprehensive analysis of five women's cases from our retrospective study of 800 women. The findings from our study emphasize the importance of addressing maternal cardiac health in pregnancy and the need for targeted interventions and improvements in the existing healthcare system to reduce adverse maternal outcomes.

Cardiovascular Disease Risk Assessment Using Traditional Risk Factors and Polygenic Risk Scores in the Million Veteran Program.

Importance: Primary prevention of atherosclerotic cardiovascular disease (ASCVD) relies on risk stratification. Genome-wide polygenic risk scores (PRSs) are proposed to improve ASCVD risk estimation. Objective: To determine whether genome-wide PRSs for coronary artery disease (CAD) and acute ischemic stroke improve ASCVD risk estimation with traditional clinical risk factors in an ancestrally diverse midlife population. Design, Setting, and Participants: This was a prognostic analysis of incident events in a retrospectively defined longitudinal cohort conducted from January 1, 2011, to December 31, 2018. Included in the study were adults free of ASCVD and statin naive at baseline from the Million Veteran Program (MVP), a mega biobank with genetic, survey, and electronic health record data from a large US health care system. Data were analyzed from March 15, 2021, to January 5, 2023. Exposures: PRSs for CAD and ischemic stroke derived from cohorts of largely European descent and risk factors, including age, sex, systolic blood pressure, total cholesterol, high-density lipoprotein (HDL) cholesterol, smoking, and diabetes status. Main Outcomes and Measures: Incident nonfatal myocardial infarction (MI), ischemic stroke, ASCVD death, and composite ASCVD events. Results: A total of 79 151 participants (mean [SD] age, 57.8 [13.7] years; 68 503 male [86.5%]) were included in the study. The cohort included participants from the following harmonized genetic ancestry and race and ethnicity categories: 18 505 non-Hispanic Black (23.4%), 6785 Hispanic (8.6%), and 53 861 non-Hispanic White (68.0%) with a median (5th-95th percentile) follow-up of 4.3 (0.7-6.9) years. From 2011 to 2018, 3186 MIs (4.0%), 1933 ischemic strokes (2.4%), 867 ASCVD deaths (1.1%), and 5485 composite ASCVD events (6.9%) were observed. CAD PRS was associated with incident MI in non-Hispanic Black (hazard ratio [HR], 1.10; 95% CI, 1.02-1.19), Hispanic (HR, 1.26; 95% CI, 1.09-1.46), and non-Hispanic White (HR, 1.23; 95% CI, 1.18-1.29) participants. Stroke PRS was associated with incident stroke in non-Hispanic White participants (HR, 1.15; 95% CI, 1.08-1.21). A combined CAD plus stroke PRS was associated with ASCVD deaths among non-Hispanic Black (HR, 1.19; 95% CI, 1.03-1.17) and non-Hispanic (HR, 1.11; 95% CI, 1.03-1.21) participants. The combined PRS was also associated with composite ASCVD across all ancestry groups but greater among non-Hispanic White (HR, 1.20; 95% CI, 1.16-1.24) than non-Hispanic Black (HR, 1.11; 95% CI, 1.05-1.17) and Hispanic (HR, 1.12; 95% CI, 1.00-1.25) participants. Net reclassification improvement from adding PRS to a traditional risk model was modest for the intermediate risk group for composite CVD among men (5-year risk >3.75%, 0.38%; 95% CI, 0.07%-0.68%), among women, (6.79%; 95% CI, 3.01%-10.58%), for age older than 55 years (0.25%; 95% CI, 0.03%-0.47%), and for ages 40 to 55 years (1.61%; 95% CI, -0.07% to 3.30%). Conclusions and Relevance: Study results suggest that PRSs derived predominantly in European samples were statistically significantly associated with ASCVD in the multiancestry midlife and older-age MVP cohort. Overall, modest improvement in discrimination metrics were observed with addition of PRSs to traditional risk factors with greater magnitude in women and younger age groups.

Apolipoprotein E genetic variation, atherogenic index and cardiovascular disease risk assessment in an African population: An analysis of HIV and malaria patients in Ghana.

BACKGROUND: Apolipoprotein E is involved in lipid transport and clearance of lipoprotein through low-density lipoprotein receptors (LDLR). ApoE variation has been linked to cardiovascular disease (CVD) risk. There are 3 isoforms of ApoE which originate from two non-synonymous single nucleotide polymorphisms denoted as ε2, ε3 and ε4. The ε2 isoform is implicated in higher levels of atherogenic lipoprotein with the ε4 isoform causing LDLR downregulation. This leads to variable effects and differential CVD risk. Malaria and HIV are life-threatening diseases affecting several countries globally especially in sub-Saharan Africa. Parasite and viral activities have been implicated in lipid dysregulation leading to dyslipidaemia. This study examined ApoE variation and CVD risk assessment in malaria and HIV patients. METHODS: We compared 76 malaria-only, 33 malaria-HIV coinfected, 21-HIV-only and 31 controls from a tertiary health facility in Ghana. Fasting venous blood samples were taken for ApoE genotyping and lipid measurements. Clinical and laboratory data were collected with ApoE genotyping performed using Iplex Gold microarray and PCR-RFLP. Cardiovascular disease risk was calculated using the Framingham BMI and cholesterol risk and Qrisk3 tools. RESULTS: The frequency of C/C genotype for rs429358 was 9.32%, whiles T/T genotype for rs7412 was found in 2.48% of all participants. ε3/ε3 was the most distributed ApoE genotype accounting for 51.55% of the total participants whiles ε2/ε2 was found in 2.48% of participants, with 1 in malaria-only and 3 in HIV-only patients. There was a significant association between ε4+ and high TG (OR = 0.20, CI; 0.05-0.73; p = 0.015), whiles ε2+ was significantly associated with higher BMI (OR; 0.24, CI; 0.06-0.87; p = 0.030) and higher Castelli Risk Index II in females (OR = 11.26, CI; 1.37-92.30; p = 0.024). A higher proportion of malaria-only participants had a moderate to high 10-year CVD risk. CONCLUSION: Overall malaria patients seem to have a higher CVD risk though the means through which this occurs may be poorly understood. ε2/ε2 genotypes was observed in our population at a lower frequency. Further studies are vital to determine CVD risk in malaria and how this occurs.

A computational framework of routine test data for the cost-effective chronic disease prediction.

Chronic diseases, because of insidious onset and long latent period, have become the major global disease burden. However, the current chronic disease diagnosis methods based on genetic markers or imaging analysis are challenging to promote completely due to high costs and cannot reach universality and popularization. This study analyzed massive data from routine blood and biochemical test of 32 448 patients and developed a novel framework for cost-effective chronic disease prediction with high accuracy (AUC 87.32%). Based on the best-performing XGBoost algorithm, 20 classification models were further constructed for 17 types of chronic diseases, including 9 types of cancers, 5 types of cardiovascular diseases and 3 types of mental illness. The highest accuracy of the model was 90.13% for cardia cancer, and the lowest was 76.38% for rectal cancer. The model interpretation with the SHAP algorithm showed that CREA, R-CV, GLU and NEUT% might be important indices to identify the most chronic diseases. PDW and R-CV are also discovered to be crucial indices in classifying the three types of chronic diseases (cardiovascular disease, cancer and mental illness). In addition, R-CV has a higher specificity for cancer, ALP for cardiovascular disease and GLU for mental illness. The association between chronic diseases was further revealed. At last, we build a user-friendly explainable machine-learning-based clinical decision support system (DisPioneer: http://bioinfor.imu.edu.cn/dispioneer) to assist in predicting, classifying and treating chronic diseases. This cost-effective work with simple blood tests will benefit more people and motivate clinical implementation and further investigation of chronic diseases prevention and surveillance program.

Single-cell transcriptomics for the assessment of cardiac disease.

Cardiovascular disease is the leading cause of death globally. An advanced understanding of cardiovascular disease mechanisms is required to improve therapeutic strategies and patient risk stratification. State-of-the-art, large-scale, single-cell and single-nucleus transcriptomics facilitate the exploration of the cardiac cellular landscape at an unprecedented level, beyond its descriptive features, and can further our understanding of the mechanisms of disease and guide functional studies. In this Review, we provide an overview of the technical challenges in the experimental design of single-cell and single-nucleus transcriptomics studies, as well as a discussion of the type of inferences that can be made from the data derived from these studies. Furthermore, we describe novel findings derived from transcriptomics studies for each major cardiac cell type in both health and disease, and from development to adulthood. This Review also provides a guide to interpreting the exhaustive list of newly identified cardiac cell types and states, and highlights the consensus and discordances in annotation, indicating an urgent need for standardization. We describe advanced applications such as integration of single-cell data with spatial transcriptomics to map genes and cells on tissue and define cellular microenvironments that regulate homeostasis and disease progression. Finally, we discuss current and future translational and clinical implications of novel transcriptomics approaches, and provide an outlook of how these technologies will change the way we diagnose and treat heart disease.

Integrating the Biology of Cardiovascular Disease into the Epidemiology of Economic Decision Modelling via Mendelian Randomisation.

Health economic analyses are essential for health services research, providing decision-makers and payers with evidence about the value of interventions relative to their opportunity cost. However, many health economic approaches are still limited, especially regarding the primary prevention of cardiovascular disease (CVD). In this article, we discuss some limitations to current health economic models and then outline an approach to address these via the incorporation of genomics into the design of health economic models for CVD. We propose that when a randomised clinical trial is not possible or practical, health economic models for primary prevention of CVD can be based on Mendelian randomisation analyses, a technique to assess causality in observational data. We discuss the advantages of this approach, such as integrating well-known disease biology into health economic models and how this may overcome current statistical approaches to assessing the benefits of interventions. We argue that this approach may provide the economic argument for integrating genomics into clinical practice and the efficient targeting of newer therapeutics, transforming our approach to the primary prevention of CVD, thereby moving from reactive to preventive healthcare. We end by discussing some limitations and potential pitfalls of this approach.

Cost-Effectiveness of Polygenic Risk Scores to Guide Statin Therapy for Cardiovascular Disease Prevention.

BACKGROUND: Atherosclerotic cardiovascular diseases (CVDs) are leading causes of death despite effective therapies and result in unnecessary morbidity and mortality throughout the world. We aimed to investigate the cost-effectiveness of polygenic risk scores (PRS) to guide statin therapy for Canadians with intermediate CVD risk and model its economic outlook. METHODS: This cost-utility analysis was conducted using UK Biobank prospective cohort study participants, with recruitment from 2006 to 2010, and at least 10 years of follow-up. We included nonrelated white British-descent participants (n=96 116) at intermediate CVD risk with no prior lipid lowering medication or statin-indicated conditions. A coronary artery disease PRS was used to inform decision to use statins. The effects of statin therapy with and without PRS, as well as CVD events were modelled to determine the incremental cost-effectiveness ratio from a Canadian public health care perspective. We discounted future costs and quality-adjusted life-years by 1.5% annually. RESULTS: The optimal economic strategy was when intermediate risk individuals with a PRS in the top 70% are eligible for statins while the lowest 1% are excluded. Base-case analysis at a genotyping cost of $70 produced an incremental cost-effectiveness ratio of $172 906 (143 685 USD) per quality-adjusted life-year. In the probabilistic sensitivity analysis, the intervention has approximately a 50% probability of being cost-effective at $179 100 (148 749 USD) per quality-adjusted life-year. At a $0 genotyping cost, representing individuals with existing genotyping information, PRS-guided strategies dominated standard care when 12% of the lowest PRS individuals were withheld from statins. With improved PRS predictive performance and lower genotyping costs, the incremental cost-effectiveness ratio demonstrates possible cost-effectiveness under thresholds of $150 000 and possibly $50 000 per quality-adjusted life-year. CONCLUSIONS: This study suggests that using PRS alongside existing guidelines might be cost-effective for CVD. Stronger predictiveness combined with decreased cost of PRS could further improve cost-effectiveness, providing an economic basis for its inclusion into clinical care.

Pre-clinical assessment of SLN360, a novel siRNA targeting LPA, developed to address elevated lipoprotein (a) in cardiovascular disease.

BACKGROUND AND AIMS: The LPA gene encodes apolipoprotein (a), a key component of Lp(a), a potent risk factor for cardiovascular disease with no specific pharmacotherapy. Here we describe the pharmacological data for SLN360, a GalNAc-conjugated siRNA targeting LPA, designed to address this unmet medical need. METHODS: SLN360 was tested in vitro for LPA knockdown in primary hepatocytes. Healthy cynomolgus monkeys received single or multiple subcutaneous doses of the SLN360 sequence ranging from 0.1 to 9.0 mg/kg to determine the pharmacokinetic and pharmacodynamic effects. Liver mRNA and serum biomarker analyses were performed. RESULTS: In vitro, the SLN360 sequence potently reduces LPA mRNA in primary cynomolgus and human hepatocytes, while no effect was observed on the expression of APOB or PLG. In vivo, SLN360 exposure peaks 2 h after subcutaneous injection with near full elimination by 24 h. Specific LPA mRNA reduction (up to 91% 2 weeks after dosing) was observed with only the 3 mg/kg group showing appreciable return to baseline (40%). No consistent dose- or time-dependent effect on the expression of APOB, PLG or a panel of sensitive markers of liver lipid accumulation was observed. Potent (up to 95%) and long lasting (≥9 weeks) serum Lp(a) reduction was observed, peaking in all active groups at day 21. The minimally effective dose was determined to be 0.3 mg/kg with an ED50 of 0.6 mg/kg. CONCLUSIONS: SLN360 induces a sustained reduction in serum Lp(a) levels in cynomolgus monkeys following subcutaneous dosing. SLN360 has potential to address the unmet need of Lp(a) reduction in cardiovascular diseases.

Health Disparities of Cardiometabolic Disorders Among Filipino Americans: Implications for Health Equity and Community-Based Genetic Research.

Health disparities are well-documented among different racial and ethnic minority groups in the United States. Filipino Americans (FAs) are the third-largest Asian-American group in the USA and are commonly grouped under the Asian categorization. FAs have a higher prevalence of cardiometabolic disorders than non-Hispanic Whites and other Asian subgroups with rates comparable to African Americans. Although no major epidemiological studies have ascertained the prevalence of cardiometabolic diseases in FAs, limited reports suggest that FAs have a higher prevalence of dyslipidemia, hypertension, diabetes, metabolic syndrome, hyperuricemia, and gout than non-FAs. A recent genetic study has shown that FAs could have the highest prevalence of a genetic polymorphism strongly associated with the development of gout and gout-related comorbidities. While developing cardiometabolic disorders is a heterogeneous and multifaceted process, the overall prevalence of certain cardiometabolic disorders parallel the prevalence of population-level risk factors, including genetics, dietary lifestyles, health beliefs, and social determinants of health. Therefore, assessment of the Filipino cuisine, health behaviors among Filipinos, socio-cultural factors, and acculturation to living in the USA are equally critical. Ascertaining the contribution of the biological causes to disease onset and the different psychosocial factors that could modulate disease risk or disease management are needed. Ultimately, a multilevel research approach is critical to assess the role of biological and non-biological risk factors of cardiometabolic disorders in FAs to inform culturally appropriate health promotion, disease prevention strategies, and a personalized approach to health.

Peripheral blood RNA biomarkers for cardiovascular disease from bench to bedside: a position paper from the EU-CardioRNA COST action CA17129.

Despite significant advances in the diagnosis and treatment of cardiovascular diseases, recent calls have emphasized the unmet need to improve precision-based approaches in cardiovascular disease. Although some studies provide preliminary evidence of the diagnostic and prognostic potential of circulating coding and non-coding RNAs, the complex RNA biology and lack of standardization have hampered the translation of these markers into clinical practice. In this position paper of the CardioRNA COST action CA17129, we provide recommendations to standardize the RNA development process in order to catalyse efforts to investigate novel RNAs for clinical use. We list the unmet clinical needs in cardiovascular disease, such as the identification of high-risk patients with ischaemic heart disease or heart failure who require more intensive therapies. The advantages and pitfalls of the different sample types, including RNAs from plasma, extracellular vesicles, and whole blood, are discussed in the sample matrix, together with their respective analytical methods. The effect of patient demographics and highly prevalent comorbidities, such as metabolic disorders, on the expression of the candidate RNA is presented and should be reported in biomarker studies. We discuss the statistical and regulatory aspects to translate a candidate RNA from a research use only assay to an in-vitro diagnostic test for clinical use. Optimal planning of this development track is required, with input from the researcher, statistician, industry, and regulatory partners.

Genetic Risk Assessment for Atherosclerotic Cardiovascular Disease: A Guide for the General Cardiologist.

Genetic testing for cardiovascular (CV) disease has had a profound impact on the diagnosis and evaluation of monogenic causes of CV disease, such as hypertrophic and familial cardiomyopathies, long QT syndrome, and familial hypercholesterolemia. The success in genetic testing for monogenic diseases has prompted special interest in utilizing genetic information in the risk assessment of more common diseases such as atherosclerotic cardiovascular disease (ASCVD). Polygenic risk scores (PRS) have been developed to assess the risk of coronary artery disease, which now include millions of single-nucleotide polymorphisms that have been identified through genomewide association studies. Although these PRS have demonstrated a strong association with coronary artery disease in large cross-sectional population studies, there remains intense debate regarding the added value that PRS contributes to existing clinical risk prediction models such as the pooled cohort equations. In this review, we provide a brief background of genetic testing for monogenic drivers of CV disease and then focus on the recent developments in genetic risk assessment of ASCVD, including the use of PRS. We outline the genetic testing that is currently available to all cardiologists in the clinic and discuss the evolving sphere of specialized cardiovascular genetics programs that integrate the expertise of cardiologists, geneticists, and genetic counselors. Finally, we review the possible implications that PRS and pharmacogenomic data may soon have on clinical practice in the care for patients with or at risk of developing ASCVD.

Equity in Genomics: A Brief Report on Cardiovascular Health Disparities in African American Adults.

BACKGROUND: African Americans are more likely to die from cardiovascular disease (CVD) than all other populations in the United States. Although technological advances have supported rapid growth in applying genetics/genomics to address CVD, most research has been conducted among European Americans. The lack of African American representation in genomic samples has limited progress in equitably applying precision medicine tools, which will widen CVD disparities if not remedied. PURPOSE: This report summarizes the genetic/genomic advances that inform precision health and the implications for cardiovascular disparities in African American adults. We provide nurse scientists recommendations for becoming leaders in developing precision health tools that promote population health equity. CONCLUSIONS: Genomics will continue to drive advances in CVD prevention and management, and equitable progress is imperative. Nursing should leverage the public's trust and its widespread presence in clinical and community settings to prevent the worsening of CVD disparities among African Americans.

Panels des maladies cardiovasculaires héréditaires par séquençage de nouvelle génération: rapport d'évaluation sur le rapatriement d'analyses réalisées hors Québec / Rapport d'évaluation sur le rapatriement d'analyses réalisées hors Québec

VALIDITÉ ET UTILITÉ CLINIQUE: Le choix des gènes de l'offre provinciale de diagnostic moléculaire des maladies cardiovasculaires héréditaires a été effectué en s'appuyant notamment sur la littérature scientifique et sur des ressources largement reconnues telles que PanelApp (Genomics England, Royaume-Uni) et ClinGen (National Institutes of Health, États-Unis). Sur la base des données locales préliminaires, le rendement diagnostique des analyses proposées serait d'environ 14 % pour les arythmies et de 22 % pour les cardiomyopathies héréditaires. Les données pour les aortopathies n'étaient pas disponibles au moment de la rédaction de ce rapport. Outre la confirmation d'une étiologie génétique, l'identification d'un variant pathologique ou probablement pathologique permet d'évaluer le pronostic, de cibler le dépistage familial et d'adapter la prise en charge médicale des patients concernés. Chez les personnes atteintes de cardiomyopathie et d'arythmie importantes ou à risque connu d'arythmie, un défibrillateur automatique implantable peut être envisagé. Quinze documents publiés par des sociétés savantes ont permis d'étayer l'utilité clinique de ces analyses moléculaires. On retient que les panels de gènes ou le séquençage de l'exome entier jouent un rôle important dans le diagnostic, la gestion et la surveillance des maladies cardiovasculaires héréditaires. Ce type d'analyse a notamment fait l'objet de recommandations favorables de remboursement public en Australie, en France et au Royaume-Uni. Néanmoins, certaines suggestions relatives aux critères cliniques, aux libellés employés dans les algorithmes et à l'exhaustivité des analyses pour certaines conditions cardiovasculaires ont été proposées par les experts consultés. Par ailleurs, certains experts sont d'avis qu'il serait pertinent d'envisager l'ajout des gènes précédemment identifiés comme potentiellement associés à une condition cardiovasculaire héréditaire par les laboratoires externes, et ce, pour assurer une offre de service adaptée aux besoins des populations locales. Lors des consultations, des préoccupations d'ordre plus générique et non spécifiquement applicables aux panels des maladies cardiovasculaires ont également été relevées. Certaines de ces préoccupations font référence aux processus de demande d'analyses et à la validation de leur pertinence, à la formation des prescripteurs, aux modalités de transmission des rapports, à l'accès au dossier médical du patient, à l'absence de politiques claires sur la gestion et la divulgation des variants de signification incertaine, à la réanalyse de ceux-ci et à la diffusion des rapports modifiés. ANALYSE ÉCONOMIQUE DEUX: rapports d'évaluation des technologies en santé dont les conclusions quant à l'analyse de l'efficience semblent transférables au contexte québécois ont été repérés. Selon les auteurs, les panels d'arythmies héréditaires et de cardiomyopathies par SNG seraient efficients par rapport aux soins usuels, mais ils soulignent le niveau d'incertitude important de ces résultats. En ce qui concerne l'analyse d'impact budgétaire, selon les hypothèses retenues, le rapatriement de l'ensemble des analyses moléculaires par SNG pour le diagnostic des maladies cardiovasculaires héréditaires pourrait générer des économies de près de 1,2 M$ sur trois ans afin de servir les patients de l'ensemble du Québec. Ces économies pourraient varier de près de 750 000 $ à 1,8 M$. CONCLUSION: Le présent rapport est fondé sur une revue rapide de la littérature scientifique et grise de même que sur la perspective d'experts. Il vise à outiller le MSSS dans sa décision de rapatrier les panels de gènes destinés au diagnostic moléculaire des maladies cardiovasculaires héréditaires. Dans le cadre du présent exercice, aucun enjeu important n'a été relevé, et l'information recueillie soutient la pertinence de rapatrier ces analyses. Toutefois, certaines préoccupations liées aux besoins des populations locales et à l'organisation des services entourant la réalisation de ces analyses au Québec ont été mises en lumière et devraient être explorées pour assurer une implantation optimale. Les conclusions sur les économies potentielles annoncées suggèrent également la prudence.

BACKGROUND AND MANDATE: Requests for authorization of medical laboratory services that are not available in Québec are mainly for high-throughput simultaneous sequencing of multiple genes using the socalled next-generation approach. The province's laboratories have the technology and expertise to perform these tests. With a view to achieving economies of scale and promoting more judicious use of these services, the Ministère de la Santé et des Services sociaux (MSSS) has undertaken to quickly repatriate several tests performed using nextgeneration sequencing (NGS), under the governance of the Réseau québécois de diagnostic moléculaire (RQDM). The rollout of this vast project undoubtedly entails opportunities and risks with respect to the overall offer of service and requires reflection in this regard. At the MSSS's request, the Institut national d'excellence en santé et en services sociaux (INESSS) is conducting a rapid assessment of the relevance of, the issues surrounding and, when appropriate, the optimal implementation mechanisms for the repatriation of these tests, from the overall perspective of Québec's healthcare system. The present report deals specifically with NGS gene panels for the molecular diagnosis of hereditary cardiovascular diseases: cardiomyopathies, arrythmias and aortopathies. METHOD: The process included a rapid review of the scientific and grey literature regarding the clinical and economic aspects, a budget impact analysis, and consultations with Québec experts. Only documents containing synthesis data or recommendations concerning the use of an NGS test to diagnose hereditary cardiovascular diseases were retained. INESSS set up an advisory committee, whose members were invited to express their views on the different issues associated with the repatriation of the proposed tests. The final findings are based on the triangulation of the scientific data, the positions of the main learned societies consulted, and the contextual data and experiential knowledge gathered. CLINICAL CONTEXTS AND PROPOSED TESTS: Cardiovascular diseases are a very heterogeneous group of disorders that can be acquired or inherited. The hereditary forms include the familial cardiomyopathies, arrhythmias and aortopathies. The mode of transmission and penetrance vary according to the phenotypic group and the gene involved. Therefore, to identify or confirm the genetic etiology of a hereditary cardiovascular disease (genotype/phenotype correlation), the requester is proposing the rollout of an offer of service that includes 17 virtual panels of genes associated with the different phenotypic groups of hereditary arrhythmias, cardiomyopathies and aortopathies. These panels will be analyzed using the sequencing data on 445 genes, of which a maximum of 97 will be reported on in the context of the current knowledge. VALIDITY AND CLINICAL UTILITY: The genes for the provincial offer of molecular diagnosis of hereditary cardiovascular diseases were chosen mainly on the basis of the scientific literature and widely recognized resources, such as PanelApp (Genomics England, UK) and ClinGen (National Institutes of Health, USA). Based on preliminary local data, the diagnostic performance of the proposed tests is approximately 14% for hereditary arrhythmias and 22% for hereditary cardiomyopathies. Data for the aortopathies were not available at the time of writing. In addition to confirming a genetic etiology, identifying a pathological or likely pathological variant enables one to assess the prognosis, target family screening and tailor the medical management of the patients concerned. In individuals with significant cardiomyopathy or arrhythmia or at known risk of arrhythmia, an implantable automatic defibrillator might be considered. Fifteen learned society publications support the clinical utility of these molecular tests. It is recognized that gene panels and whole-exome sequencing play an important role in the diagnosis, management and monitoring of hereditary cardiovascular diseases. This type of testing has, in fact, received favourable public coverage recommendations in Australia, France and the United Kingdom. Implementation considerations The experts consulted and the literature agree that genetic testing should be prioritized on the basis of a combination of clinical presentation and family history information. In this regard, to support the rollout of this offer of service and the optimal use of these tests, a clinical algorithm is presented. A prior medical genetics or cardiogenetics consultation is recommended in order to assess the presence of clinical and paraclinical criteria and guide the choice of molecular tests accordingly. Given that this service is already offered to patients at the Institut de cardiologie de Montréal and that procedures for sending specimens outside Québec are used for patients at other institutions, an impact on their continuum of care or a significant increase in demand is not anticipated. In light of the consultations held, the offer of service appears to be generally in line with the needs. Nevertheless, certain suggestions regarding the clinical criteria, the wording used in the algorithms, and the thoroughness of the testing for certain cardiovascular conditions were offered by the experts consulted. In addition, some experts felt that it would be useful to consider adding genes previously identified as being potentially associated with a hereditary cardiovascular condition by outside laboratories, in order to ensure an offer of service tailored to the needs of the local populations. Also, concerns of a more generic nature that do not specifically pertain to cardiovascular disease panels were raised during the consultations. Some of these concerns were about the procedures for ordering tests, the validation of their appropriateness, the training of prescribers, reporting procedures, access to the patient's medical records, the lack of clear policies on the management and disclosure of variants of uncertain significance, retesting for these variants, and the dissemination of modified reports. ECONOMIC ANALYSIS: Two health technology assessment reports were identified whose conclusions regarding the cost-effectiveness analysis seem to be transferable to the Québec context. According to their authors, hereditary arrhythmia and cardiomyopathy NGS panels are more costeffective than the usual care, but they mention the significant level of uncertainty in these results. As for the budget impact analysis, depending on the assumptions made, repatriating all of the NGS molecular tests for the diagnosis of hereditary cardiovascular diseases could generate savings of close to $1.2 million over 3 years for serving patients throughout Québec. These savings could range from around $750,000 to $1.8 million. CONCLUSION: This report is based on a rapid review of the scientific and grey literature and on the expert perspective. It is intended to assist the MSSS in its decision to repatriate the gene panels for the molecular diagnosis of hereditary cardiovascular diseases. In this exercise, no major issues were identified, and the information gathered supports the appropriateness of repatriating these tests. However, certain concerns pertaining to the needs of local populations and the organization of the services surrounding the execution of these tests in Québec were raised and should be explored to ensure optimal implementation. Also, the conclusions regarding the stated potential savings should be viewed with caution.

Current trends in epidemiology of cardiovascular disease and cardiovascular risk management in type 2 diabetes.

With the advances in diabetes care, the trend of incident cardiovascular disease (CVD) in patients with type 2 diabetes mellitus (T2DM) has been decreasing over past decades. However, given that CVD is still a major cause of death in patients with diabetes and that the risk of CVD in patients with T2DM is more than twice that in those without DM, there are still considerable challenges to the prevention of CVD in diabetes. Accordingly, there have been several research efforts to decrease cardiovascular (CV) risk in T2DM. Large-scale genome-wide association studies (GWAS) and clinical cohort studies have investigated the effects of factors, such as genetic determinants, hypoglycaemia, and insulin resistance, on CVD and can account for the unexplained CV risk in T2DM. Lifestyle modification is a widely accepted cornerstone method to prevent CVD as the first-line strategy in T2DM. Recent reports from large CV outcome trials have proven the positive CV effects of sodium-glucose cotransporter-2 (SGLT-2) inhibitors and glucagon-like peptide-1 receptor agonists (GLP-1RAs) in patients with high CVD risk. Overall, current practice guidelines for the management of CVD in T2DM are moving from a glucocentric strategy to a more individualised patient-centred approach. This review will discuss the current epidemiologic trends of CVD in T2DM and the risk factors linking T2DM to CVD, including genetic contribution, hypoglycaemia, and insulin resistance, and proper care strategies, including lifestyle and therapeutic approaches.

Differences in the Platelet mRNA Landscape Portend Racial Disparities in Platelet Function and Suggest Novel Therapeutic Targets.

The African American (AA) population displays a 1.6 to 3-fold higher incidence of thrombosis and stroke mortality compared with European Americans (EAs). Current antiplatelet therapies target the ADP-mediated signaling pathway, which displays significant pharmacogenetic variation for platelet reactivity. The focus of this study was to define underlying population differences in platelet function in an effort to identify novel molecular targets for future antiplatelet therapy. We performed deep coverage RNA-Seq to compare gene expression levels in platelets derived from a cohort of healthy volunteers defined by ancestry determination. We identified > 13,000 expressed platelet genes of which 480 were significantly differentially expressed genes (DEGs) between AAs and EAs. DEGs encoding proteins known or predicted to modulate platelet aggregation, morphology, or platelet count were upregulated in AA platelets. Numerous G-protein coupled receptors, ion channels, and pro-inflammatory cytokines not previously associated with platelet function were likewise differentially expressed. Many of the signaling proteins represent potential pharmacologic targets of intervention. Notably, we confirmed the differential expression of cytokines IL32 and PROK2 in an independent cohort by quantitative real-time polymerase chain reaction, and provide functional validation of the opposing actions of these two cytokines on collagen-induced AA platelet aggregation. Using Genotype-Tissue Expression whole blood data, we identified 516 expression quantitative trait locuses with Fst values > 0.25, suggesting that population-differentiated alleles may contribute to differences in gene expression. This study identifies gene expression differences at the population level that may affect platelet function and serve as potential biomarkers to identify cardiovascular disease risk. Additionally, our analysis uncovers candidate novel druggable targets for future antiplatelet therapies.