Development of sensitive and specific age- and gender-specific low-density lipoprotein cholesterol cutoffs for diagnosis of first-degree relatives with familial hypercholesterolaemia in cascade testing
-
Brian Starr
Abstract
Background: The plasma total and low-density lipoprotein-cholesterol (LDL-C) levels that are used as diagnostic criteria for familial hypercholesterolaemia (FH) probands in the general population are too stringent for use in relatives, given the higher prior probability of a first-degree relative being FH (50% vs. 1/500). Our objective was therefore to develop more appropriate LDL-C cutoffs to identify “affected” first-degree relatives found by cascade testing, to test their accuracy and utility in case identification, and to compare them with the published “Make early diagnosis to prevent disease” (MEDPED) cutoffs from the US.
Methods: Using a large, anonymised sample of genetically tested first-degree relatives of Netherlands FH probands (mutation carriers/non-carriers, n=825/2469), age- and gender-specific LDL-C diagnostic cutoffs for first-degree relatives were constructed. These were used to test similar data from Denmark (n=160/161) and Norway (n=374/742).
Results: Gender-specific LDL-C diagnostic cutoffs were established for six different age groups, which achieved an overall accuracy (measured as Youden's index) of 0.53 in the Netherlands data, and performed significantly better amongst younger (<25 years) compared to older first-degree relatives (0.68 vs. 0.42 Youden's index, p<0.001). Compared with the Netherlands data, age- and gender-adjusted mean LDL-C levels were significantly higher (approximately 0.5 mmol/L) in the Denmark and Norway subjects for both mutation carriers and non-carriers. After adjusting for this difference, the LDL-C cut-offs showed a similar accuracy in identifying mutation carriers from Denmark (81%, range 78%–86%) and Norway (84%, range 82%–86%). Although the MEDPED cutoffs performed significantly worse than these for the Netherlands data (p<0.001), they performed equally well in overall accuracy for the Norwegian and Danish data, although the LDL-C cutoffs had a significantly higher sensitivity but lower specificity for all three countries.
Conclusions: The cutoffs developed here are designed to give the greatest overall accuracy when testing relatives of FH patients in the absence of a genetic diagnosis. They have a more balanced specificity and sensitivity than the MEDPED cutoffs that are designed to achieve higher specificity, which is more appropriate for cascade testing purposes. The data suggest that country-specific LDL-C cutoffs may lead to greater accuracy for identifying FH patients, but should be used with caution and only when a genetic diagnosis (DNA) is not available.
Clin Chem Lab Med 2008;46:791–803.
©2008 by Walter de Gruyter Berlin New York
Articles in the same Issue
- Reviews
- The STANISLAS Cohort: a 10-year follow-up of supposed healthy families. Gene-environment interactions, reference values and evaluation of biomarkers in prevention of cardiovascular diseases
- Cardiovascular biomarkers: increasing impact of laboratory medicine in cardiology practice
- Haemolysis: an overview of the leading cause of unsuitable specimens in clinical laboratories
- Cardiovascular Diseases
- APOA5 Ala315>Val, identified in patients with severe hypertriglyceridemia, is a common mutation with no major effects on plasma lipid levels
- Gender-modulated impact of apolipoprotein A5 gene (APOA5) −1131T>C and c.56C>G polymorphisms on lipids, dyslipidemia and metabolic syndrome in Turkish adults
- Oxidative stress markers, C-reactive protein and heat shock protein 70 levels in subjects with metabolic syndrome
- Development of sensitive and specific age- and gender-specific low-density lipoprotein cholesterol cutoffs for diagnosis of first-degree relatives with familial hypercholesterolaemia in cascade testing
- Distribution of plasma cardiac troponin I values in healthy subjects: pathophysiological considerations
- High-density lipoprotein cholesterol and paraoxonase 1 (PON1) genetics and serum PON1 activity in prepubertal children in Spain
- Genetics and Molecular Diagnostics
- Polymorphisms of CYP17A1, CYP19, and androgen in Brazilian women with uterine leiomyomas
- A novel MEN1 frameshift germline mutation in two Italian monozygotic twins
- The silent hemoglobin α chain variant Hb Riccarton [α51(CE9)Gly→Ser] may affect HbA1c determination on the HLC-723 G7 analyzer
- General Clinical Chemistry and Laboratory Medicine
- Urinary fructose-1,6-bisphosphatase activity as a marker of the damage to the renal proximal tubules in children with idiopathic nephrotic syndrome
- Antioxidant defense capacity in scleroderma patients
- Correction of ventricular cerebrospinal fluid (CSF) samples for blood content does not increase sensitivity and specificity for the detection of CSF infection
- Validation and Outcome Studies
- Preanalytical quality control program – an overview of results (2001–2005 summary)
- A laboratory-based risk score for medical intensive care patients
- Analytical performance evaluation of the Cobas 6000 analyzer – special emphasis on trueness verification
- Letters to the Editor
- Quality planning and analytical quality requirements derived from biology
- Importance of sample size in hospital point-of-care glucose measurements
- Reliability of M protein quantification: comparison of two peak integration methods on Capillarys 2
- What's in a name? Standardization of HbA1c
- Serum paraoxonase 1 activities and homocysteinemia in hemodialysis patients
Articles in the same Issue
- Reviews
- The STANISLAS Cohort: a 10-year follow-up of supposed healthy families. Gene-environment interactions, reference values and evaluation of biomarkers in prevention of cardiovascular diseases
- Cardiovascular biomarkers: increasing impact of laboratory medicine in cardiology practice
- Haemolysis: an overview of the leading cause of unsuitable specimens in clinical laboratories
- Cardiovascular Diseases
- APOA5 Ala315>Val, identified in patients with severe hypertriglyceridemia, is a common mutation with no major effects on plasma lipid levels
- Gender-modulated impact of apolipoprotein A5 gene (APOA5) −1131T>C and c.56C>G polymorphisms on lipids, dyslipidemia and metabolic syndrome in Turkish adults
- Oxidative stress markers, C-reactive protein and heat shock protein 70 levels in subjects with metabolic syndrome
- Development of sensitive and specific age- and gender-specific low-density lipoprotein cholesterol cutoffs for diagnosis of first-degree relatives with familial hypercholesterolaemia in cascade testing
- Distribution of plasma cardiac troponin I values in healthy subjects: pathophysiological considerations
- High-density lipoprotein cholesterol and paraoxonase 1 (PON1) genetics and serum PON1 activity in prepubertal children in Spain
- Genetics and Molecular Diagnostics
- Polymorphisms of CYP17A1, CYP19, and androgen in Brazilian women with uterine leiomyomas
- A novel MEN1 frameshift germline mutation in two Italian monozygotic twins
- The silent hemoglobin α chain variant Hb Riccarton [α51(CE9)Gly→Ser] may affect HbA1c determination on the HLC-723 G7 analyzer
- General Clinical Chemistry and Laboratory Medicine
- Urinary fructose-1,6-bisphosphatase activity as a marker of the damage to the renal proximal tubules in children with idiopathic nephrotic syndrome
- Antioxidant defense capacity in scleroderma patients
- Correction of ventricular cerebrospinal fluid (CSF) samples for blood content does not increase sensitivity and specificity for the detection of CSF infection
- Validation and Outcome Studies
- Preanalytical quality control program – an overview of results (2001–2005 summary)
- A laboratory-based risk score for medical intensive care patients
- Analytical performance evaluation of the Cobas 6000 analyzer – special emphasis on trueness verification
- Letters to the Editor
- Quality planning and analytical quality requirements derived from biology
- Importance of sample size in hospital point-of-care glucose measurements
- Reliability of M protein quantification: comparison of two peak integration methods on Capillarys 2
- What's in a name? Standardization of HbA1c
- Serum paraoxonase 1 activities and homocysteinemia in hemodialysis patients
