At present, there have been various FH clinical criteria available for various populations but there is scarcity of known gold standard criteria to diagnose FH. To the best of our knowledge, this is the first study to demonstrate the ability of various clinical criteria to identify positive FH cases in an Asian population. We applied the DLCC as the reference diagnostic criteria to identify index cases because it is largely used in our clinical settings; its similarities to the SB Register criteria and its ability to predict presence of genetic mutations despite a weak phenotype-genotype concordance, [19]. Moreover, it uses lower cut of level for LDL-c with additional indicators such as arcus cornealis, peripheral vascular disease and premature cerebral disease when compared to other criteria, in which potentially greater FH cases will be identified.
In low-middle income Asian countries, routine genetic testing is technically demanding and costly. Similarly, genetic mutation confirmation parameter was not done for our study due to the financial constraint, which is commonly observed practice in Malaysia. Elucidating diagnostic performances of various clinical FH criteria, without the use of genetic testing is particularly useful for Malaysia and other Asian populations. Factors such as family or personal history of tendon xanthoma and LDL-c was found to be strongly associated with positive genetic diagnosis in a Spanish population, in which a thorough examination for tendon xanthoma in suspected FH patients were recommended prior genetic testing [14]. A recent study analyzing 5050 subjects from a UK database recommended an assessment tool algorithm in order to improve the detection of FH in primary care setting prior to referral for genetic testing [20]. The JFHMC is the only established FH diagnostic criteria for use in the Japanese population and genetic testing is not used to diagnose FH but without validation in other Asian population.
This study found that the SB Register criteria identified more individuals with FH compared to the US MEDPED and the JFHMC when assessed against the DLCC. All of the criteria had a high specificity but low sensitivity values. Nevertheless, the SB Register criteria had the highest sensitivity compared to the US MEDPED and the JFHMC (51.1% vs. 25.3% vs. 47.0%; p < 0.001). The low sensitivity or the poor performance in finding the true positive of FH cases according to the DLCC by the SB Register criteria could be explained by the difficulty of getting a complex family history in order to fulfill the diagnosis of positive FH. Similarly, the US MEDPED and the JFHMC require information on family history of premature CAD and relative’s serum cholesterol values to be classified as positive FH. Hence, complex clinical history may deter the performance of these criteria in detecting FH.
Our study found a high positive predictive (98.1% vs. 98.1% vs. 97.9%) but lower negative predictive values (62.3% vs. 56.1% vs. 60.4%) by the SB Register criteria, the US MEDPED and the JFHMC respectively. This could be explained by the fact that most of the subjects were identified from tertiary and lipid specialist care, in which prevalence of FH is higher than the general population. Therefore, the interpretation of the reliability of each criteria to predict true positive FH and true negative FH must be done with caution.
Although the US MEDPED is a simple diagnostic criterion, it was found to be successful in diagnosing only 25.3% of those diagnosed with FH when compared against the DLCC. It had the lowest sensitivity and efficiency value compared to other criteria. Furthermore, the majority of its No FH cases were reclassified as definite FH by the DLCC. The JFHMC had better sensitivity, specificity and efficiency value compared to the US MEDPED. The low diagnostic efficiency values in all of the criteria against the DLCC suggests that the SB Register, the US MEDPED and the JFHMC could not identify positive and negative FH accurately when compared to the DLCC. Future studies comparing these various criteria against results of genetic testing are required to strengthen the recommendation for genetic testing to confirm FH cases detected clinically.
To date, an excess of over 1000 genetic variants have been identified in the Low Density Lipoprotein-Receptor gene (LDLR), Apolipoprotein B-100 gene (APOB), or Proprotein Convertase Subtilisin/Kexin type 9 gene (PCSK9) [21]. Molecular diagnosis is often difficult except in populations where only a limited number of mutations predominate. We postulate that genetic testing would post a challenge in finding true FH cases due to the presence of vast spectrum of genetic variants in the multiethnic heterogenous population of Malaysia. Given that genetic testing is costly and not readily accessible in many countries, a need to identify the best phenotype indication to achieve accurate yield is required. This would be useful in determining the gold standard criteria for detecting FH in a Malaysian population.