Overview of a collaborative global effort to address the burden of familial hypercholesterolaemia.

This is an overview of the EAS Familial Hypercholesterolaemia (FH) Studies Collaboration (FHSC) global consortium and registry (established 2015), which broadly addresses the global burden of FH. Eighty-seven National Lead Investigators from 74 countries form this expanding global consortium, and this global registry currently includes pooled data on 70,000 participants from participating countries to facilitate FH surveillance. Published first results from this global registry concluded that FH is diagnosed late, and management of LDL-cholesterol falls below guideline recommendations, and therefore earlier detection of FH and wider use of combination therapy is required. Further FHSC studies will follow on updated data including new countries, participants and variables, and non-DNA genetic information, and on the remaining cohorts in the registry. FHSC cross-sectional collaborative global studies are expected to promote FH detection earlier in life to subsequently initiate early lipid lowering therapy to reduce lifelong exposure to cumulative LDL-cholesterol thus reducing cardiovascular disease risk.

Ensemble machine learning methods in screening electronic health records: A scoping review.

Background: Electronic health records provide the opportunity to identify undiagnosed individuals likely to have a given disease using machine learning techniques, and who could then benefit from more medical screening and case finding, reducing the number needed to screen with convenience and healthcare cost savings. Ensemble machine learning models combining multiple prediction estimates into one are often said to provide better predictive performances than non-ensemble models. Yet, to our knowledge, no literature review summarises the use and performances of different types of ensemble machine learning models in the context of medical pre-screening. Method: We aimed to conduct a scoping review of the literature reporting the derivation of ensemble machine learning models for screening of electronic health records. We searched EMBASE and MEDLINE databases across all years applying a formal search strategy using terms related to medical screening, electronic health records and machine learning. Data were collected, analysed, and reported in accordance with the PRISMA scoping review guideline. Results: A total of 3355 articles were retrieved, of which 145 articles met our inclusion criteria and were included in this study. Ensemble machine learning models were increasingly employed across several medical specialties and often outperformed non-ensemble approaches. Ensemble machine learning models with complex combination strategies and heterogeneous classifiers often outperformed other types of ensemble machine learning models but were also less used. Ensemble machine learning models methodologies, processing steps and data sources were often not clearly described. Conclusions: Our work highlights the importance of deriving and comparing the performances of different types of ensemble machine learning models when screening electronic health records and underscores the need for more comprehensive reporting of machine learning methodologies employed in clinical research.

The time is now: Achieving FH paediatric screening across Europe - The Prague Declaration.

Familial hypercholesterolaemia (FH) is the most common inherited metabolic disorder characterized by high cholesterol and if left untreated leads to premature cardiovascular disease, such as heart attacks. Treatment that begins early in life, particularly in childhood, is highly efficacious in preventing cardiovascular disease and cost-effective, thus early detection of FH is crucial. However, in Europe, less than 10% of people living with FH are diagnosed and even less receive life-saving treatment. The Prague Declaration is a call to action for national and European Union policymakers and decision-makers and a result of the Czech EU Presidency meeting on FH Paediatric Screening (early detection of inherited high cholesterol) at the Czech Senate in Prague on 6th September 2022. It builds on a considerable body of evidence which was discussed at the Technical Meeting under the auspices of the Slovenian EU Presidency in October 2021. The Prague meeting addressed the outstanding barriers to the systematic implementation of FH paediatric screening across Europe. In this article, we present the key points from the Prague meeting and concrete actions needed to move forward.

Paediatric familial hypercholesterolaemia screening in Europe: public policy background and recommendations.

Familial hypercholesterolaemia (FH) is under-recognized and under-treated in Europe leading to significantly higher risk for premature heart disease in those affected. As treatment beginning early in life is highly effective in preventing heart disease and cost-effective in these patients, screening for FH is crucial. It has therefore now been recognized by the European Commission Public Health Best Practice Portal as an effective strategy. Model programmes exist in Europe to identify young individuals with FH, which are based on cascade screening of first-degree relatives of affected individuals, universal screening for high cholesterol, opportunistic screening of high-risk individuals, or a combination of the above approaches. Recommendations presented herein to improve identification of FH emphasize that every country should have an FH screening programme. These programmes should be adapted from existing strategies to best fit the individual country's healthcare system, governments should provide financial support for these programmes and related care, and further research to optimize care and implementations should be conducted.

Effect of computerised, knowledge-based, clinical decision support systems on patient-reported and clinical outcomes of patients with chronic disease managed in primary care settings: a systematic review.

OBJECTIVES: Chronic diseases are the leading cause of disability globally. Most chronic disease management occurs in primary care with outcomes varying across primary care providers. Computerised clinical decision support systems (CDSS) have been shown to positively affect clinician behaviour by improving adherence to clinical guidelines. This study provides a summary of the available evidence on the effect of CDSS embedded in electronic health records on patient-reported and clinical outcomes of adult patients with chronic disease managed in primary care. DESIGN AND ELIGIBILITY CRITERIA: Systematic review, including randomised controlled trials (RCTs), cluster RCTs, quasi-RCTs, interrupted time series and controlled before-and-after studies, assessing the effect of CDSS (vs usual care) on patient-reported or clinical outcomes of adult patients with selected common chronic diseases (asthma, chronic obstructive pulmonary disease, heart failure, myocardial ischaemia, hypertension, diabetes mellitus, hyperlipidaemia, arthritis and osteoporosis) managed in primary care. DATA SOURCES: Medline, Embase, CENTRAL, Scopus, Health Management Information Consortium and trial register clinicaltrials.gov were searched from inception to 24 June 2020. DATA EXTRACTION AND SYNTHESIS: Screening, data extraction and quality assessment were performed by two reviewers independently. The Cochrane risk of bias tool was used for quality appraisal. RESULTS: From 5430 articles, 8 studies met the inclusion criteria. Studies were heterogeneous in population characteristics, intervention components and outcome measurements and focused on diabetes, asthma, hyperlipidaemia and hypertension. Most outcomes were clinical with one study reporting on patient-reported outcomes. Quality of the evidence was impacted by methodological biases of studies. CONCLUSIONS: There is inconclusive evidence in support of CDSS. A firm inference on the intervention effect was not possible due to methodological biases and study heterogeneity. Further research is needed to provide evidence on the intervention effect and the interplay between healthcare setting features, CDSS characteristics and implementation processes. PROSPERO REGISTRATION NUMBER: CRD42020218184.

A mixed-method service evaluation of health information exchange in England: technology acceptance and barriers and facilitators to adoption.

BACKGROUND: The need for information exchange and integrated care has stimulated the development of interoperability solutions that bring together patient data across the health and care system to enable effective information sharing. Health Information Exchange (HIE) solutions have been shown to be effective in supporting patient care, however, user adoption often varies among users and care settings. This service evaluation aimed to measure user acceptance of HIE and explore barriers and facilitators to its wider uptake. METHODS: A mixed-method study design was used. A questionnaire was developed using the Unified Theory of Acceptance and Use of Technology and administered to HIE users to assess technology acceptance. Pearson Chi2 tests were used to examine differences in acceptance between user groups and care settings. Web-based, semi-structured interviews were conducted drawing on the Normalisation Process Theory to explore barriers and facilitators to adoption. Interview data were analysed thematically using the Framework Approach. RESULTS: A total of 105 HIE users completed the survey and another 12 participated in the interviews. Significant differences were found in HIE acceptance between users groups and care settings, with high adopters demonstrating higher acceptance and social care users showing lower acceptance. Participants identified several drivers to adoption, including increased information accessibility, better care coordination, informed decision-making, improved patient care, reduced duplication of procedures, and time and cost savings. However, they also highlighted a number of barriers, such as lack of awareness about the solution and its value, suboptimal communication strategies, inadequate training and lack of resources for knowledge dissemination, absence of champions to support the implementation, lack of end-user involvement in the implementation and evaluation of HIE, unclear accountability and responsibility for the overall success of the programme, and patient confidentiality concerns. CONCLUSIONS: Working to better engage stakeholders, considering the needs of users from different care settings, providing users with training resources and support to increase their knowledge and confidence in using the system, developing implementation strategies to seek user feedback and monitor performance, and using communication strategies to increase awareness of the product and its value, can help improve uptake and adoption of HIE.

A meta-analysis of medications directed against PCSK9 in familial hypercholesterolemia.

BACKGROUND AND AIMS: Several medications targeting PCSK9 reduce LDL-cholesterol (LDL-C) in heterozygous familial hypercholesterolemia (HeFH). We aimed to assess in patients diagnosed clinically as HeFH, whether LDL-C reduction varied by different therapeutic approaches to PCSK9-targeting or by the underlying genetic variant. METHODS: We conducted a random-effects meta-analysis of randomised clinical trials assessing PCSK9-targeting therapies, namely alirocumab, evolocumab and inclisiran, in patients with clinically diagnosed HeFH and restricted analyses to those patients in whom genotypic data were available. A search of MEDLINE and Embase identified eligible trials published between inception and June 29, 2020. We included trials of sufficient duration to allow for a stable treatment effect: ~12 weeks for monoclonal antibodies (mAbs) (alirocumab, evolocumab) and ~1 year for small interfering RNA (siRNA) (inclisiran). Single-moderator meta-regression comparing mean percentage LDL-C reduction between mAbs and siRNA as well as PCSK9-targeting therapies between different genotypes was used to assess heterogeneity. RESULTS: Eight trials of HeFH met our inclusion criteria, including 1887 genotyped patients. Among monogenic HeFH cases (N = 1347) the LDL-C reduction from baseline was 46.12% (95%CI 48.4-43.9) for siRNA and 50.4% (59.3-41.4) for mAbs compared to control, without evidence of significant heterogeneity between treatment (QM = 0.32, df = 1, p = 0.57). Irrespective of therapeutic approach to PCSK9-targeting, reductions in LDL-C were generally consistent across genetic variants (LDL-Receptor variants, LDL-Receptor variants of unknown significance, Apolipoprotein B variants, two variants and no variant) (QM = 8.3, df = 4, p = 0.08). CONCLUSIONS: Among patients with HeFH, the LDL-C-lowering effect of PCSK9-targeting medications did not show statistical heterogeneity across different drug-classes and across genetic variants.

Prevalence of Familial Hypercholesterolemia Among the General Population and Patients With Atherosclerotic Cardiovascular Disease: A Systematic Review and Meta-Analysis.

BACKGROUND: Contemporary studies suggest that familial hypercholesterolemia (FH) is more frequent than previously reported and increasingly recognized as affecting individuals of all ethnicities and across many regions of the world. Precise estimation of its global prevalence and prevalence across World Health Organization regions is needed to inform policies aiming at early detection and atherosclerotic cardiovascular disease (ASCVD) prevention. The present study aims to provide a comprehensive assessment and more reliable estimation of the prevalence of FH than hitherto possible in the general population (GP) and among patients with ASCVD. METHODS: We performed a systematic review and meta-analysis including studies reporting on the prevalence of heterozygous FH in the GP or among those with ASCVD. Studies reporting gene founder effects and focused on homozygous FH were excluded. The search was conducted through Medline, Embase, Cochrane, and Global Health, without time or language restrictions. A random-effects model was applied to estimate the overall pooled prevalence of FH in the general and ASCVD populations separately and by World Health Organization regions. RESULTS: From 3225 articles, 42 studies from the GP and 20 from populations with ASCVD were eligible, reporting on 7 297 363 individuals/24 636 cases of FH and 48 158 patients/2827 cases of FH, respectively. More than 60% of the studies were from Europe. Use of the Dutch Lipid Clinic Network criteria was the commonest diagnostic method. Within the GP, the overall pooled prevalence of FH was 1:311 (95% CI, 1:250-1:397; similar between children [1:364] and adults [1:303], P=0.60; across World Health Organization regions where data were available, P=0.29; and between population-based and electronic health records-based studies, P=0.82). Studies with ≤10 000 participants reported a higher prevalence (1:200-289) compared with larger cohorts (1:365-407; P<0.001). The pooled prevalence among those with ASCVD was 18-fold higher than in the GP (1:17 [95% CI, 1:12-1:24]), driven mainly by coronary artery disease (1:16; [95% CI, 1:12-1:23]). Between-study heterogeneity was large (I2>95%). Tests assessing bias were nonsignificant (P>0.3). CONCLUSIONS: With an overall prevalence of 1:311, FH is among the commonest genetic disorders in the GP, similarly present across different regions of the world, and is more frequent among those with ASCVD. The present results support the advocacy for the institution of public health policies, including screening programs, to identify FH early and to prevent its global burden.

Familial hypercholesterolemia: is it time to separate monogenic from polygenic familial hypercholesterolemia?

PURPOSE OF REVIEW: This review explores the concepts of monogenic and the so-called polygenic familial hypercholesterolemia and how the identification of familial hypercholesterolemia as a monogenic condition and its separation from polygenic primary hypercholesterolemia may have implications for clinical practice. RECENT FINDINGS: Through genetic testing, a mutation in any of the three known autosomal dominant familial hypercholesterolemia-causing genes is found in 60-80% of cases with a clinical diagnosis of definite familial hypercholesterolemia. As individuals with a polygenic basis for their hypercholesterolemia do not follow the same inheritance pattern observed in monogenic familial hypercholesterolemia, the use of family-based cascade screening in individuals with a polygenic origin is not recommend, as only 30% of relatives have an elevated LDL-C compared to the 50% in monogenic families. The presence of a causative monogenic mutation associates the highest cardiovascular risk vs. not having a mutation or having a polygenic background, providing prognostic information independent of LDL-C. It may also help assess intensity of interventions. Treatment adherence also seems to be higher after monogenic confirmation of hypercholesterolemia. SUMMARY: Knowledge about the genetic status of an individual with clinical familial hypercholesterolemia (monogenic vs. polygenic) can provide a more informed understanding to evaluating risk, managing disease and opportunities for screening strategies.

Sustainability of 'mHealth' interventions in sub- Saharan Africa: a stakeholder analysis of an electronic community case management project in Malawi.

Background: The global health community and funding agencies are currently engaged in ensuring that worthwhile research-based programmes are sustainable. Despite its importance, few studies have analysed the sustainability of global health interventions. In this paper, we aim to explore barriers and facilitators for the wider implementation and sustainability of a mobile health (mHealth) intervention (Supporting LIFE Community Case Management programme) in Malawi, Africa. Methods: Between January and March 2017, a qualitative approach was used to carry out and analyse 13 in-depth semi-structured interviews with key stakeholders across all levels of healthcare provision in Malawi to explore their perceptions with regards to the implementation and sustainability of the mHealth programme. Data were analysed thematically by two reviewers. Results: Overall, our analysis found that the programme was successful in achieving its goals. However, there are many challenges to the wider implementation and sustainability of this programme, including the absence of monetary resources, limited visibility outside the healthcare sector, the lack of integration with community-based and nationwide programmes, services and information and communication technologies, and the limited local capacity in relation to the maintenance, further development, and management. Conclusions: Future developments should be aligned with the strategic goals and interests of the Ministry of Health and engage with national and international stakeholders to develop shared goals and strategies for nationwide scale-up. These developments should also focus on building local capacity by educating trainers and ensuring that training methods and guidelines are appropriately accredited based on national policies. Our findings provide a framework for a variety of stakeholders who are engaged in sustaining mHealth programmes in resource-poor settings and can be used to develop an evidence-based policy for the utilization of technology for healthcare delivery across developing countries.

American Heart Association's Cholesterol CarePlan as a Smartphone-Delivered Web App for Patients Prescribed Cholesterol-Lowering Medication: Protocol for an Observational Feasibility Study.

BACKGROUND: Adoption of healthy lifestyle and compliance with cholesterol-lowering medication reduces the risk of cardiovascular disease (CVD). The use of digital tools and mobile technology may be important for sustaining positive behavioral change. OBJECTIVE: The primary objective of this study is to evaluate the feasibility and acceptability of administering the Cholesterol CarePlan Web app developed by the American Heart Association aimed at improving lifestyle and medication adherence among patients prescribed cholesterol-lowering medication. The secondary objective is to assess the Web app's efficacy. METHODS: A prospective, observational feasibility study will be conducted to demonstrate whether the Web app may be successfully taken up by patients and will be associated with improved clinical and behavioral outcomes. The study will aim to recruit 180 study participants being prescribed cholesterol-lowering medication for at least 30 days across 14 general practices in London, England. Potentially eligible patients will be invited to use the Web app on a smartphone and visit general practice for three 20-minute clinical assessments of blood pressure, height, weight, smoking, and nonfasting cholesterol over 24 weeks. The feasibility of administering the Web app will be judged by recruitment and dropout statistics and the sociodemographic and comorbidity profile of consenting study participants, consenting nonparticipants, and all potentially eligible patients. Acceptability will be assessed using patients' readiness to embrace new technologies, the usability of the Web app, and patient satisfaction. The efficacy of the Web app will be assessed by changes in medication adherence and clinical risk factors by levels of the Web app compliance. RESULTS: This study is currently funded by the American Heart Association. Initial study recruitment will take place between February and July 2018 followed by patient follow-up. Patient level data will be obtained in January 2019. Data analysis will be completed by February 2019. Results will be submitted for publication in March 2019. CONCLUSIONS: The potential of an app to improve patients' lifestyle and management of cholesterol may inform the design of a randomized controlled trial and the delivery of more effective CVD prevention programs. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): PRR1-10.2196/9017.