PDF(Pubmed)
Abstract：
BACKGROUND: Familial hypercholesterolemia (FH) is predominantly caused by mutations in the 4 FH candidate genes (FHCGs), namely, low-density lipoprotein receptor (LDLR), apolipoprotein B-100 (APOB-100), proprotein convertase subtilisin/kexin type 9 (PCSK9), and the LDL receptor adaptor protein 1 (LDLRAP1). It is characterized by elevated low-density lipoprotein cholesterol (LDL-c) levels leading to premature coronary artery disease. FH can be clinically diagnosed using established clinical criteria, namely, 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 (1) compare the detection rate of genetically confirmed FH and diagnostic accuracy between the FAMCAT, SB, and DLCC in the Malaysian primary care setting; (2) identify the genetic mutation profiles, including novel variants, in individuals with suspected FH in primary care; (3) explore the experience, concern, and expectation of individuals with suspected FH who have undergone genetic testing in primary care; and (4) evaluate the clinical utility of a web-based FH Identification Tool that includes the 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 1, the diagnostic accuracy study design is used to compare the detection rate and diagnostic accuracy of the FAMCAT, SB, and DLCC against molecular diagnosis as the gold standard. In Work stream 2, the targeted next-generation sequencing of the 4 FHCGs is used to identify the genetic mutation profiles among individuals with suspected FH. In Work stream 3a, a qualitative semistructured interview methodology is used to explore the experience, concern, and expectation of individuals with suspected FH who have undergone genetic testing. Lastly, in Work stream 3b, a qualitative real-time observation of primary care physicians using the \"think-aloud\" methodology is applied to evaluate the clinical utility of a web-based FH Identification Tool.
RESULTS: The recruitment for Work stream 1, and blood sampling and genetic analysis for Work stream 2 were completed in February 2023. Data collection for Work stream 3 was completed in March 2023. Data analysis for Work streams 1, 2, 3a, and 3b is projected to be completed by 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 criterion is the best to detect FH in the Malaysian primary care setting. The full spectrum of genetic mutations in the FHCGs including novel pathogenic variants will be identified. Patients\' perspectives while undergoing genetic testing and the primary care physicians experience in utilizing the web-based tool will be established. These findings will have tremendous impact on the management of patients with FH in primary care and subsequently reduce their risk of premature coronary artery disease.
UNASSIGNED: DERR1-10.2196/47911.
OBJECTIVE: This study aims to (1) compare the detection rate of genetically confirmed FH and diagnostic accuracy between the FAMCAT, SB, and DLCC in the Malaysian primary care setting; (2) identify the genetic mutation profiles, including novel variants, in individuals with suspected FH in primary care; (3) explore the experience, concern, and expectation of individuals with suspected FH who have undergone genetic testing in primary care; and (4) evaluate the clinical utility of a web-based FH Identification Tool that includes the 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 1, the diagnostic accuracy study design is used to compare the detection rate and diagnostic accuracy of the FAMCAT, SB, and DLCC against molecular diagnosis as the gold standard. In Work stream 2, the targeted next-generation sequencing of the 4 FHCGs is used to identify the genetic mutation profiles among individuals with suspected FH. In Work stream 3a, a qualitative semistructured interview methodology is used to explore the experience, concern, and expectation of individuals with suspected FH who have undergone genetic testing. Lastly, in Work stream 3b, a qualitative real-time observation of primary care physicians using the \"think-aloud\" methodology is applied to evaluate the clinical utility of a web-based FH Identification Tool.
RESULTS: The recruitment for Work stream 1, and blood sampling and genetic analysis for Work stream 2 were completed in February 2023. Data collection for Work stream 3 was completed in March 2023. Data analysis for Work streams 1, 2, 3a, and 3b is projected to be completed by 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 criterion is the best to detect FH in the Malaysian primary care setting. The full spectrum of genetic mutations in the FHCGs including novel pathogenic variants will be identified. Patients\' perspectives while undergoing genetic testing and the primary care physicians experience in utilizing the web-based tool will be established. These findings will have tremendous impact on the management of patients with FH in primary care and subsequently reduce their risk of premature coronary artery disease.
UNASSIGNED: DERR1-10.2196/47911.
摘要：
背景：家族性高胆固醇血症（FH）主要由四个FH候选基因（FHCG）即低密度脂蛋白受体（LDLR）的突变引起，载脂蛋白B-100(APOB-100),前蛋白转化酶枯草杆菌蛋白酶/kexin9型（PCSK9）LDL受体衔接蛋白1（LDLRAP1）。其特征在于低密度脂蛋白胆固醇(LDL-c)升高,导致过早冠状动脉疾病(CAD)。FH可以使用既定的临床标准进行临床诊断，即西蒙·布鲁姆（SB）和荷兰脂质临床标准（DLCC），并且可以使用家族性高胆固醇血症病例诊断工具（FAMCAT）进行识别，初级保健筛查工具。
目的：本研究旨在i）比较FAMCAT之间遗传证实的FH的检出率和诊断准确性，马来西亚初级保健环境中的SB和DLCC；ii)识别基因突变谱，包括新颖的变体，在初级保健中疑似FH的个体中；iii)探索经验，对在初级保健中接受基因检测的疑似FH患者的关注和期望；iv)评估包括FAMCAT在内的基于网络的FH识别工具的临床实用性，SB,和DLCC在马来西亚初级保健环境中。
方法：这是在马来西亚中央行政区的11个卫生部初级保健诊所进行的混合方法评估研究。在工作流（WS）1中，诊断准确性研究设计用于比较FAMCAT的检测率和诊断准确性，SB和DLCC反对分子诊断为金标准。在WS2中，四种FHCG的靶向下一代测序用于鉴定疑似FH个体中的基因突变谱。在WS3a中，采用定性的半结构化访谈方法来探索经验，对已接受基因检测的疑似FH个体的关注和期望。最后,在WS3b中，使用“大声思考”方法对初级保健医生进行定性实时观察，以评估基于网络的FH识别工具的临床实用性。
结果：WS1的招募，WS2的血液采样和遗传分析于2023年2月完成。WS3的数据收集于2023年3月完成。WS1、2、3a和3b的数据分析预计将于2023年6月完成，这项研究的结果预计将于2023年12月公布。
结论：这项研究将提供证据，证明在马来西亚初级保健机构中，临床诊断标准是检测FH的最佳方法。将鉴定FHCG中的遗传突变的全谱,包括新的致病变体。将建立接受基因检测的患者观点和初级保健医生在使用基于网络的工具方面的经验。这些发现将对FH患者的初级保健管理产生巨大影响，并随后降低其早发CAD的风险。
目的：本研究旨在i）比较FAMCAT之间遗传证实的FH的检出率和诊断准确性，马来西亚初级保健环境中的SB和DLCC；ii)识别基因突变谱，包括新颖的变体，在初级保健中疑似FH的个体中；iii)探索经验，对在初级保健中接受基因检测的疑似FH患者的关注和期望；iv)评估包括FAMCAT在内的基于网络的FH识别工具的临床实用性，SB,和DLCC在马来西亚初级保健环境中。
方法：这是在马来西亚中央行政区的11个卫生部初级保健诊所进行的混合方法评估研究。在工作流（WS）1中，诊断准确性研究设计用于比较FAMCAT的检测率和诊断准确性，SB和DLCC反对分子诊断为金标准。在WS2中，四种FHCG的靶向下一代测序用于鉴定疑似FH个体中的基因突变谱。在WS3a中，采用定性的半结构化访谈方法来探索经验，对已接受基因检测的疑似FH个体的关注和期望。最后,在WS3b中，使用“大声思考”方法对初级保健医生进行定性实时观察，以评估基于网络的FH识别工具的临床实用性。
结果：WS1的招募，WS2的血液采样和遗传分析于2023年2月完成。WS3的数据收集于2023年3月完成。WS1、2、3a和3b的数据分析预计将于2023年6月完成，这项研究的结果预计将于2023年12月公布。
结论：这项研究将提供证据，证明在马来西亚初级保健机构中，临床诊断标准是检测FH的最佳方法。将鉴定FHCG中的遗传突变的全谱,包括新的致病变体。将建立接受基因检测的患者观点和初级保健医生在使用基于网络的工具方面的经验。这些发现将对FH患者的初级保健管理产生巨大影响，并随后降低其早发CAD的风险。
