Familial hypercholesterolemia (FH) is a genetic lipoprotein disorder characterized by elevations in low-density lipoprotein cholesterol (LDL-C) >95th percentile for age and gender. Affected individuals may show clinical manifestations (xanthomas, xanthelasmas and premature arcus corneus) although these manifestations are seen less frequently with early diagnosis and treatment. Untreated, FH will lead to atherosclerotic cardiovascular disease (CVD), primarily coronary artery disease (CAD). There are at least three accepted definitions for FH, based on absolute LDL-C levels (MedPed criteria), the Simon-Broome criteria include a fixed cut-point for LDL-C, the presence of DNA mutations and xanthomas and the FH Dutch Criteria (the Netherlands).
There are well-developed FH Registries in the Netherlands, United Kingdom, Spain, France, and the US, through the newly established US FH Foundation. In the United Kingdom, a report on the economic advantages of treating FH revealed that lipid-lowering statin therapy would lead to 101 fewer cardiovascular deaths/1000 patients with FH given treatment. The cost saving from cardiovascular events is estimated at over $CAN 592 million in the UK if all relatives of index cases were identified and treated, compared with no treatment given. This cascade testing strategy has been successfully applied in the Netherlands in families of FH probands with a detected mutation, thus allowing statin treatment of family members at risk of early coronary heart disease.
In Canada, the burden of disease is estimated to be approximately 83,500 patients, based on an allele frequency of 1/500. In the province of Quebec, the allele frequency is approximately 1/270 and the number of affected subjects is approximately 29,000. Left untreated, FH men develop cardiovascular disease (CVD) in the third decade of life and women, in the fourth decade. When identified and treated early, life expectancy is normal.
The purpose of this initiative is to create a registry of subjects with FH across Canada designed to identify subjects with FH and to improve health and healthcare delivery. Rare diseases of lipoprotein metabolism (orphan diseases) will also be included (SMASH registry; Systems and Molecular Approach of Severe Hyperlipidemia). This registry will include clinical, biochemical and demographic information. Specimens (plasma/serum and DNA) will be collected for biobanking. The registry will be made available for clinicians to manage patient care, identify relatives for screening and treatment (cascade screening), to provide advice to general practitioners and to support collaborative studies in biomedical, clinical, health outcomes and health economics research. Access to anonymized data from the registry will be given to researchers, clinicians, biopharmaceutical industry and government by peer-reviewed process.
The Mission of the Canadian FH Registry is to bring together a multi-disciplinary group of physicians, basic and clinical researchers to improve the delivery of care to patients with severe lipoprotein disorders, especially FH, and to foster collaborative research. Our Vision is to create a Canada-wide network of academic clinics, integrating lipid specialists, endocrinologists and cardiologists to treat patients with the highest standard of care and to create a collaborative research environment. Using a "hub and spoke" model, the registry will be extended in various communities to link primary care physicians with provincial academic centers. The Goals are to improve care to patients with FH and to reduce cardiovascular disease in this population at high risk.
Given the wide geographic distribution of patients with FH, we plan to provide a "hub and spoke" model specialized care. The hubs would be based in each province in centers recognized at the national level for their expertise in lipoprotein disorders and with advanced laboratory facilities (medical biochemistry, specialized assays, ultracentrifugation, genetic testing). Radiating from these centers will be clinics that treat patients with FH. We propose a three-tier registry (local, provincial and Canada-wide). The local database would be nominative, used solely by the clinic or center and contain the information obtained by the local investigators and used for clinical purposes. The provincial database will use encrypted numbers, without identifiers other than the provincial health insurance number, and will be used to generate province-specific health outcomes, resource utilization, health economics and comparative epidemiological/genetic/clinical features across provinces. The Canadian database would be anonymous and serve to generate country-wide statistics, public awareness and research collaborations.
All procedures related to the FH registry will follow uniform standard operation procedures (SOP). The various steps associated with the inclusion of patients within the FH Registry will be the following: subject with high LDL-C, secondary causes ruled out, FH Criteria satisfied, consent form signed, clinical evaluation, baseline lipid profile, demographic info, family history, longitudinal follow-up (annual data capture). If a patient has a family history of FH, then we will start cascade screening. If the FH criteria are not satisfied at the beginning of the study then the patient will be asked to enter in the SMASH registry for other severe disorders of the lipid metabolism.
The database software should fulfill the following criteria: if must comply with privacy regulations in all provinces, use passwords that allow limited access, with access tailored to each site. It must allow researchers access under strictly controlled conditions after peer-review. The software must be flexible enough to allow easy data entry and capture for the provincial and Canadian databases. Cost considerations are also an issue. The choice of software has not been made yet.
Biobanking will be performed at individual sites, when available. Plasma/serum, DNA, tissues (e.g. skin biopsies) will be potentially included. The consent form will have a specific section dealing with DNA banking and the possibility that the DNA may be sent to a central laboratory for analysis. The informed consent will also stipulate that plasma/serum and DNA samples may be analyzed by academic collaborators outside of Canada and by industry (pharmaceutical and/or biotechnology).
Data entry at each site will be performed using nominative information and coded specific to the institution (hospital ID number). In addition, each subject's provincial health insurance number will be entered and a unique identifier will be assigned (for instance BC_000001; QC_000001 and so on). As FH is highly familial by nature, parents, sibs and all first-degree relatives of each subject will also be entered, if known. While each subject will have a distinct identifier, family relationships will be recorded. Completely anonymous data will be made available to researchers, policy makers, governments and industry on a per need basis. Physicians at each site will be able to retrieve the information pertinent to their site only. Access to the database will be granted after investigators have submitted a written request to the Scientific Board and clearance will be given in consultation with the Advisory Board. Both levels of government (provincial and National) will be given similar access, as will the pharmaceutical industry and the biopharmaceutical industry.
Potential benefits Patients. Patients will have access to expert care in the field of lipoprotein disorders and CVD prevention. In many cases, optimal treatment of severe hypercholesterolemia may be best provided by experts in the field. They will have access to on-going clinical trials and to novel therapies. Furthermore, individual patients will be offered family screening to identify affected members who would benefit from early diagnosis and treatment. The identification of new FH cases by cascade screening proves to be both cost-effective and aligns with the aim of providing personalized medicine for patients with severe lipoprotein disorders.
Clinicians. The registry will provide the local (i.e. clinic or hospital) framework to diagnose patients according to accepted international criteria for FH, to follow the subjects in time and to perform cascade screening (first, second and third-degree relatives), a cost-effective strategy to screen potentially affected subjects. The registry will also link clinicians into a network of specialized clinics that favor collaborative investigator-initiated research and participation in multi-center studies. The availability of biobanking will allow the storage of plasma/serum and DNA for future research.
Biomedical researchers. The identification of novel genes for FH and other rare lipoprotein disorders has led to a better understanding of metabolic pathways and eventually the potential for novel therapeutic targets. In addition, gene-gene and gene-environment interactions research may shed light on mechanisms of disease. clinical-scientists will have the opportunity to develop investigator-initiated research, using the pan-Canadian registry and biobanking resources as a platform. Researchers in health outcomes and health economics, social, gender and ethnic research will have access to the database in collaboration with provincial administrative databases.
Biopharmaceutical Industry. The biopharmaceutical industry will have access to a group of lipid experts across Canada, with links internationally, a harmonized database for subjects with FH and rare lipoprotein disorders. They will have access to a network of established clinics with a unified database. Access to the registry database will be provided after review of the intended research. This data will be important in determining health economics.
Government. This initiative will allow the development of clinical practice guidelines, to determine resource allocation according to need, the identification of rare (orphan disease) lipoprotein disorders requiring specific techniques, such as extracorporeal LDL filtration for homozygous FH. The initiative will allow the framework to set-up collaborative research under the peer-review system (HSFC, CIHR). Health outcomes and health economic studies will allow resource allocation and quality control. Finally centralized genetic testing would provide molecular diagnostics in a cost-effective manner, when required. This initiative will dovetail with the CIHR C-CHANGE initiative concerning the harmonization of cardiovascular preventive guidelines in Canada. To data, we are the only country with harmonized CVD prevention guidelines.
Knowledge translation and training. Individual academic institutions with a strong biomedical research commitment will offer undergraduate and graduate-level training in the field of lipid and lipoproteins within a country-wide collaborative research environment. Several centers will offer post-doctoral fellowships for clinicians and PhDs in lipoprotein metabolism, health outcomes and health economics research. This training of highly qualified personnel is expected to contribute to the academic and economic engine of the country. A formal training course, aligned with the National Lipid Association, will provide certification on the treatment of lipoprotein disorders. The establishment of clinical practice guidelines for adult and pediatric patients will enable clinicians to hone their clinical practice to the highest standard. By using well established conferences across Canada, the aim will be to integrate novel knowledge into the yearly conference programs across Canada and to disseminate this information to practicing physicians and health care professionals.