Familial Hypercholesterolemia Canada / Hypercholesterolemie Familiale Canada
Familial Hypercholesterolemia Canada / Hypercholesterolemie Familiale Canada
Familial hypercholesterolemia (FH) is the most frequent genetic lipoprotein disorder
 associated with premature CAD. In Canada, the burden of disease is estimated to be
 approximately 83,500 patients. The goal of this initiative is to create a registry of
 subjects with FH across Canada. Rare diseases of lipoprotein metabolism will also be
 included. Using a "hub and spoke" model, the registry will be extended in various communities
 to link primary care physicians with provincial academic centers. The registry will include
 clinical, biochemical and demographic information. Specimens (plasma/serum and DNA) will be
 collected for biobanking. We propose a three-tier registry: local, provincial and
 Canada-wide, which will be completely anonymized. 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. The data extracted
 for the provincial portion of the database will allow administrative database research that
 will provide important information to key stakeholders and permit allocation of resources. It
 will also allow a sound and uniform rationale for the use of novel therapeutic agents and
 provide expert advice to regulatory agencies. At the Canadian level, the database will allow
 clinicians and researchers to determine the burden of disease and the long-term effects of
 treatment. Through the creation of a Canada-wide network of academic clinics, integrating
 lipid specialists, endocrinologists and cardiologists, the Canadian FH registry will lead to
 significant benefits for FH patients, clinicians and researchers, biopharmaceutical industry
 and government.
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.
Inclusion Criteria:

 Diagnostic criteria for FH, which are:

 -  Family and/or personal history of high cholesterol

 -  Family and/or personal history of heart disease

 -  Abnormal growth on tendons, accumulation of fatty material in the eye Family history
 of FH Severe disorder of cholesterol and other lipids in the blood

 Exclusion Criteria:

 No exclusion criterion