JMIR Publications

ABSTRACT

Background:

Familial Hypercholesterolaemia (FH) is predominantly caused by mutations in the four FH candidate genes (FHCG) namely low-density lipoprotein receptor (LDLR), apolipoprotein B-100 (APOB-100), proprotein convertase subtilisin/kexin type 9 (PCSK9) the LDL receptor adaptor protein 1 (LDLRAP1). It is characterised by elevated low density lipoprotein cholesterol (LDL-c) leading to premature coronary artery disease (CAD). FH can be clinically diagnosed using established clinical criteria i.e., Simon Broome (SB) and Dutch Lipid Clinic Criteria (DLCC), and can be identified using the Familial Hypercholesterolemia Case Ascertainment Tool (FAMCAT), a primary care screening tool.

Objective:

This study aims to i) compare the detection rate of genetically confirmed FH and diagnostic accuracy between FAMCAT, SB and DLCC in the Malaysian primary care setting; ii) identify the genetic mutation profiles, including novel variants, in individuals with suspected FH in primary care; iii) explore the experience, concerns and expectations of individuals with suspected FH who have undergone genetic testing in primary care; and iv) evaluate the clinical utility of a web-based FH Identification Tool that includes FAMCAT, SB, and DLCC in the Malaysian primary care setting.

Methods:

This is a mixed-methods evaluation study conducted in 11 Ministry of Health primary care clinics located at the central administrative region of Malaysia. In Work Stream (WS) 1, the diagnostic accuracy study design is used to compare the detection rate and diagnostic accuracy of FAMCAT, SB and DLCC against molecular diagnosis as the gold standard. In WS 2, the targeted next generation sequencing of the four FHCG is used to identify the genetic mutation profiles among individuals with suspected FH. In WS 3a, a qualitative semi-structured interview methodology is used to explore the experience, concerns and expectations of individuals with suspected FH who have undergone genetic testing. Lastly, in WS 3b, a qualitative real-time observation of primary care physicians using ‘think aloud’ methodology is employed to evaluate the clinical utility of a web-based FH Identification Tool.

Results:

The recruitment for WS 1 and blood sampling for WS 2 have been completed. The data collection for WS 3 (qualitative studies) is currently ongoing. Data analysis for WS 1, 2, 3a and 3b is projected to complete in June 2023, with the results of this study anticipated to be published by December 2023.

Conclusions:

This study will provide evidence on which clinical diagnostic criteria is the best to detect FH in the Malaysian primary care setting. The full spectrum of genetic mutations in the FHCG including novel pathogenic variants will be identified. Patients’ perspectives while undergoing genetic testing and the primary care physicians experience in utilising the web-based tool will be established. These findings will have a tremendous impact on management of patients with FH in primary care and subsequently reduce their risk of premature CAD. Clinical Trial: Not applicable - this study is not a clinical trial.