Low-Density Lipoprotein Cholesterol Gymnastics: Exploring the Advantages and Limitations of the Friedewald, Martin-Hopkins, and Sampson Equations for Personalized Lipid Management.

BACKGROUND: The most commonly used method for low-density lipoprotein cholesterol (LDL-C) estimation is the Friedewald equation, which has notable limitations. However, more accurate methods have been proposed. This study investigates the advantages and limitations of these methods and identifies the contexts in which each equation is the most or least applicable. METHODS: A cohort of 222 individuals underwent a standard lipid profile assessment, including directly measuring their LDL-C (dLDL-C). LDL-C was also estimated using the Friedewald, Martin-Hopkins, and Sampson equations. The differences (%Delta) between the estimated and measured LDL-C were analyzed in relation to dLDL-C, high-density lipoprotein cholesterol (HDL-C), and triglyceride levels. RESULTS: The %Delta was significantly lower (p < 0.0001) for the Martin-Hopkins (-8.8 ± 9.8) and Sampson (-9.5 ± 9.2) equations compared to Friedewald (-12.2 ± 9.2). All equations increasingly underestimated LDL-C as the dLDL-C levels decreased. The %Delta of the Martin-Hopkins equation showed significant positive correlations with dLDL-C (≤130 mg/dL) and triglycerides and a significant negative correlation with HDL-C. In a subgroup of 30 individuals with extreme %Delta values, patterns of gross underestimation were observed, particularly when low LDL-C, low triglycerides, and high HDL-C coincided. CONCLUSIONS: The Martin-Hopkins equation is a superior method for LDL-C estimation and a valuable tool in precision medicine. However, clinicians and laboratory professionals must be aware of its limitations and recognize patterns that could lead to significant LDL-C underestimation. We propose an algorithm for clinical laboratories to provide personalized LDL-C assessments.

The clinical impact of estimating low-density lipoprotein cholesterol (LDL-C) using different equations in the general population.

BACKGROUND: Low-density lipoprotein cholesterol (LDL-C) is associated with atherosclerotic cardiovascular disease (ASCVD). Friedewald, Sampson, and Martin-Hopkins equations are used to calculate LDL-C. This study compares the impact of switching between these equations in a large geographically defined population. MATERIALS AND METHODS: Data for individuals who had a lipid panel ordered clinically between 2010 and 2019 were included. Comparisons were made across groups using the two-sample t-test or chi-square test as appropriate. Discordances between LDL measures based on clinically actionable thresholds were summarized using contingency tables. RESULTS: The cohort included 198,166 patients (mean age 54 years, 54% female). The equations perform similarly at the lower range of triglycerides but began to diverge at a triglyceride level of 125 mg/dL. However, at triglycerides of 175 mg/dL and higher, the Martin-Hopkins equation estimated higher LDL-C values than the Samson equation. This discordance was further exasperated at triglyceride values of 400 to 800 mg/dL. When comparing the Sampson and Friedewald equations, at triglycerides are below 175 mg/dL, 9% of patients were discordant at the 70 mg/dL cutpoint, whereas 42.4% were discordant when triglycerides are between 175 and 400 mg/dL. Discordance was observed at the clinically actionable LDL-C cutpoint of 190 mg/dL with the Friedewald equation estimating lower LDL-C than the other equations. In a high-risk subgroup (ASCVD risk score > 20%), 16.3% of patients were discordant at the clinical cutpoint of LDL-C < 70 mg/dL between the Sampson and Friedewald equations. CONCLUSIONS: Discordance at clinically significant LDL-C cutpoints in both the general population and high-risk subgroups were observed across the three equations. These results show that using different methods of LDL-C calculation or switching between different methods could have clinical implications for many patients.

Comparison of Performance of Various Calculated Low-Density Lipoprotein (LDL) Methods in the Indian Population: A Hospital-Based Study.

INTRODUCTION: In recent times, there has been a surge in proposed alternative approaches to computing low-density lipoprotein cholesterol (LDL-C), with a focus on enhancing precision, particularly within diverse demographic and clinical groups. Our aim is to assess the agreement, precision, and practicality of these methods compared to direct LDL-C measurements, with the goal of identifying the most effective approach for estimating LDL-C in the Indian context. METHODS: It is a retrospective analytical study. Lipid profile data were gathered from the laboratory and organized in Microsoft Excel for analysis. LDL-C was computed using three different methods: the Friedwald formula, the Martin-Hopkins formula, and Sampson's formula. These calculations were then compared with the direct method of LDL-C estimation in two distinct groups: when triglyceride (TG) levels were less than 400 mg/dL and when TG levels exceeded 400 mg/dL. Bland-Altman plots were generated, and concordance correlation coefficients (CCCs) were computed to determine the most suitable calculated method. RESULTS: Data from 1,776 participants were analysed and divided into two groups. In both Group 1 (TG < 400 mg/dL) and Group 2 (TG > 400 mg/dL) considering bias, limits of agreements, and correlation coefficient, as seen on the Bland-Altman and CCC, Martin-Hopkins equation was found to be performing better than Friedwald and Sampson's equation. CONCLUSION: In this study, the Martin-Hopkins formula appears to be the most appropriate choice for precise LDL-C level measurements and indicated improved accuracy and consistency in LDL-C measurements, especially in individuals with elevated TG levels. This underscores its importance in ensuring precise assessment and suitable clinical management.

Comparison between the Friedewald, Martin and Sampson Equations and LDL-C Quantification by Ultracentrifugation in a Mexican Population.

Low-density lipoprotein cholesterol (LDL-C), which makes up about 70% of the cholesterol in the blood, is critical in the formation of arteriosclerotic plaques, increasing the risk of heart disease. LDL-C levels are estimated using Friedewald, Martin and Sampson equations, though they have limitations with high triglycerides. Our aim is to compare the effectiveness of these equations versus the ultracentrifugation technique in individuals with and without dyslipidemia and identify precision. There were 113 participants, 59 healthy controls and 54 dyslipidemic patients. Samples were collected after fasting. LDL-C was estimated using the Friedewald, Martin and Sampson equations. The purified LDL-C, ultracentrifugated and dialysized control group without dyslipidemia vs. patients with coronary artery disease (CAD) showed differences in age, HDL-C, triglycerides and glucose non-HDL-C (p = 0.001 in all). There were correlations in CGWD between ultracentrifugation and Sampson R-squared (R2) = 0.791. In the dyslipidemia control group, ultracentrifugation and Friedewald R2 = 0.911. In patients with CAD, correlation between ultracentrifugation and Sampson R2 = 0.892; Bland-Altman confirmed agreement in controls without dyslipidemia. The Martin and Sampson equations are interchangeable with ultracentrifugation. Conclusion: The role of LDL analysis using precise techniques is necessary to obtain better control of disease outcomes after the use of precise therapies and suggests verifying its importance through clinical trials.

Reversible Mechanical Contraception and Endometriosis Treatment Using Stimuli-Responsive Hydrogels.

Female sterilization via fallopian tube ligation is a common procedure; However, after the operation, over 10% of women seek re-fertilization, which is frequently unsuccessful. In addition, there is evidence that fallopian tubes contribute to the spread of endometriotic tissue as they serve as channels for proinflammatory media entering the abdominal cavity via retrograde menstruation. Here, stimuli-degradable hydrogel implants are presented for the functional, biocompatible, and reversible occlusion of fallopian tubes. The hydrogel implants, designed with customized swelling properties, mechanically occlude fallopian tubes in a high-performance manner with burst pressures reaching 255-558 mmHg, exceeding normal abdominal pressures (95 mmHg). Their damage-free removal can be achieved within 30 min using near-visible UV light or a glutathione solution, employing a method akin to standard fallopian tube perfusion diagnostics. Ultrasound-guided implant placement is demonstrated using a clinical hysteroscope in a human-scale uterus model and biocompatibility in a porcine in vivo model. Importantly, the prevention of live sperm as well as endometrial cell passage through blocked fallopian tubes is demonstrated. Overall, a multifunctional system is presented that constitutes a possible means of on-demand, reversible contraception along with the first-ever mechanical approach to abdominal endometriosis prevention and treatment.

Validation of Estimated Small Dense Low-Density Lipoprotein Cholesterol Concentration in a Japanese General Population.

AIM: A high level of directly measured small dense low-density lipoprotein cholesterol (sdLDL-C) is a strong risk factor for atherosclerotic cardiovascular disease. A method for estimating sdLDL-C by using Sampson's equation that includes levels of total cholesterol, high-density lipoprotein cholesterol (HDL-C), non-HDL-C and triglycerides (TG) has recently been proposed. We investigated the validation and exploration of estimated sdLDL-C level. METHODS: The associations between measured and estimated sdLDL-C levels were investigated in 605 Japanese subjects (men/women: 280/325; mean age: 65±15 years) who received annual health check-ups in the Tanno-Sobetsu Study, a population-based cohort. RESULTS: Estimated sdLDL-C level was highly correlated with measured sdLDL-C level in all subjects (R2=0.701), nondiabetic subjects without any medication (n=254, R2=0.686) and subjects with diabetes mellitus (n=128, R2=0.721). Multivariable regression analysis showed that levels of non-HDL-C, TG and γ-glutamyl transpeptidase (γGTP) were independent predictors of measured sdLDL-C level. In a stratification of the LDL window, all of the subjects with a combination of high non-HDL-C (≥ 170 mg/dL) and high TG (≥ 150 mg/dL) had high levels of measured and estimated sdLDL-C (≥ 35 mg/dL). Furthermore, machine learning-based estimation of sdLDL-C level by artificial intelligence software, Prediction One, was substantially improved by using components of Sampson's equation (R2=0.803) and by using those components with the addition of γGTP and deletion of TC (R2=0.929). CONCLUSIONS: sdLDL-C level estimated by Sampson's equation can be used instead of measured sdLDL-C level in general practice. By building multiple machine learning models of artificial intelligence, a more accurate and practical estimation of sdLDL-C level might be possible.

Assessment of three equations to calculate plasma LDL cholesterol concentration in fasting and non-fasting hypertriglyceridemic patients.

OBJECTIVES: Low-density lipoprotein cholesterol (LDL-C) concentration was calculated for many years using the Friedewald equation, but those from Sampson and extended-Martin-Hopkins perform differently. Their accuracy in fasting hypertriglyceridemia and non-fasting state were compared and the clinical impact of implementing these equations on risk classification and on the setting of lipid treatment goals was assessed. METHODS: Seven thousand six standard lipid profiles and LDL-C concentrations measured after ultracentrifugation (uLDL-C) were retrospectively included. uLDL-C were compared to calculated LDL-C in terms of correlation, root mean square error, residual error, mean absolute deviations and cardiovascular stratification. RESULTS: In fasting state (n=5,826), Sampson equation was the most accurate, exhibited the highest percentage of residual error lower than 0.13 mmol/L (67 vs. 57 % and 63 % using Friedewald, or extended-Martin-Hopkins equations respectively) and the lowest misclassification rate. However, the superiority of this equation was less pronounced when triglyceride concentration (TG) <4.5 mmol/L were considered. In post-prandial state (n=1,180), extended-Martin-Hopkins was the most accurate equation, exhibited the highest percentage of residual error lower than 0.13 mmol/L (73 vs. 39 % and 57 % using Friedewald and Sampson equation respectively). Overall, the negative bias with Sampson equation may lead to undertreatment. Conversely, a positive bias was observed with extended Martin-Hopkins. CONCLUSIONS: None of the equations tested are accurate when TG>4.52 mmol/L. When TG<4.52 mmol/L both Sampson and Martin-Hopkins equations performed better than Friedewald. The switch to one or the other should take in account their limitations, their ease of implementation into the lab software and the proportion of non-fasting patients.

Anaphylaxis in Clinical Trials of Sublingual Immunotherapy Tablets.

BACKGROUND: There is no consensus method to identify anaphylaxis in sublingual immunotherapy (SLIT) trials. Standardized Medical Dictionary for Regulatory Activities (MedDRA) queries (SMQs) are standardized groupings of MedDRA terms used in drug safety monitoring. OBJECTIVE: To develop a method to identify potential anaphylaxis in SLIT-tablet trials using SMQ searches and case definitions of anaphylaxis adopted from the National Institute of Allergy and Infectious Disease. METHODS: The SMQ search tool contained 2 criteria including treatment-emergent adverse events (AEs): (1) narrow MedDRA terms related to anaphylaxis and (2) all AEs with broad MedDRA terms from at least 2 of 3 categories (respiratory/skin/cardiovascular) occurring on the same day. Criteria were applied to a pooled data set of all subjects from 48 timothy grass, ragweed, house dust mite, and tree SLIT-tablet trials (SLIT-tablet, N = 8200; placebo, N = 7033). Additional search strategies were any treatment-emergent AE with MedDRA preferred term "hypersensitivity" and epinephrine administrations. Identified potential cases underwent blinded independent medical expert review. Nonanaphylaxis cases were designated local AEs or mild to moderate systemic reactions. RESULTS: Using the SMQ search tool and after subsequent medical review, 8 anaphylaxis cases were identified; 3 were considered treatment-related, resulting in a proportion of anaphylaxis cases/subject of 0.02% (2 of 8200) with SLIT-tablet and 0.01% (1 of 7033) with placebo. One additional anaphylaxis case related to SLIT-tablet was identified by the preferred term "hypersensitivity." The 3 anaphylaxis cases associated with SLIT-tablet treatment were not life-threatening. The epinephrine administration rate was 17 of 8200 (0.2%) with SLIT-tablet treatment and 2 of 7033 (0.03%) with placebo. CONCLUSIONS: SMQ search criteria for identifying potential anaphylaxis related to SLIT were developed. Anaphylaxis was rare for SLIT-tablets.

Cardiovascular Risk Assessment and Control in Outpatients Evaluated by 24-hour Ambulatory Blood Pressure and Different LDL-C Equations.

INTRODUCTION: Office blood pressure (OBP) and low-density lipoprotein cholesterol (LDL-C) calculated by the Friedewald formula (F) are the cornerstones of the cardiovascular risk (CVR) assessment and management based on the SCORE2/SCORE2-OP model proposed by the 2021 ESC Guidelines on Cardiovascular Disease Prevention. AIM: We compared the CVR stratification estimated by the old SCORE and the SCORE2/SCORE2-OP using OBP and ambulatory blood pressure measurement (ABPM), and we evaluated the prevalence of LDL-C control, after calculating it using three validated equations, in outpatients referred for arterial hypertension. METHODS: A cross-sectional study on 1539 consecutive patients with valid ABPM. LDL-C was calculated using the Friedewald formula (F), its modification by Martin (M), and the Sampson (S) equation. SCORE and SCORE2/SCORE2-OP were estimated using OBP, mean daytime (+ 5 mmHg adjustment), and mean 24-hour systolic blood pressure (+ 10 mmHg adjustment). Individual CVR by 2021 ESC Guidelines (and SCORE2/SCORE2-OP) was compared to the 2019 ESC/EAS Guidelines (and SCORE). Differences in the prevalence of LDL-C control according to the three methods to calculate LDL-C were also analysed. RESULTS: Mean age was 60 ± 12 years, with male prevalence (54%). Mean LDL-C values were 118 ± 38 mg/dL (F), 119 ± 37 mg/dL (M), and 120 ± 38 mg/dL (S), respectively. Within the same population, SCORE and SCORE2/SCORE2-OP significantly varied, but no differences emerged after comparing the average SCORE2/SCORE2-OP calculated with OBP (6% IQR 3-10), mean 24-hour systolic BP (7% IQR 4-11), and mean daytime systolic BP (7% IQR 4-11). SCORE2/SCORE2-OP and 2021 ESC Guidelines reclassified the CVR independently of the method used for BP measurement. The low-moderate risk group decreased by 32%, whereas the high and veryhighrisk groups increased by 18% and 12%, respectively. We found a significant reduction in reaching the LDL-C goals regardless of the equation used to calculate it, except for those > 65 years, in whom results were confirmed only by using the M. CONCLUSION: SCORE2/SCORE2-OP and 2021 ESC Guidelines recommendations led to a non-negligible CVR reclassification and subsequent lack of LDL-C goal, regardless of estimating SCORE2 using OBP or ABPM. Calculating the LDL-C with the M may be the best choice in specific settings.

Correlation of extended Martin/Hopkins equation with a direct homogeneous assay in assessing low-density lipoprotein cholesterol in patients with hypertriglyceridemia.

BACKGROUND: The Friedewald or Martin/Hopkins equation is widely used to estimate low-density lipoprotein cholesterol (LDL-C) at triglyceride (TG) levels <400 mg/dL. In this study, we aimed to validate the recently developed Sampson and extended Martin/Hopkins equations intended for use in patients with TG levels up to 800 mg/dL by comparing them to a direct homogenous assay. METHODS: In total, 8676 participants with serum TG levels <800 mg/dL were enrolled in this study. LDL-C was directly measured using Abbott homogeneous assay (DLDL) and estimated using the Friedewald (FLDL), Martin/Hopkins (MLDL), extended Martin/Hopkins (EMLDL), and Sampson equations (SLDL). The overall concordance between the DLDL and LDL-C estimates was calculated. The performance of the four equations was also compared using Bland-Altman plots and mean absolute difference (MAD). RESULTS: The EMLDL was more accurate than other LDL-C equations particularly for patients with TG≥400 mg/dL (MAD = 10.43; vs. FLDL: MAD = 21.1; vs. SLDL: MAD 11.62). The overall concordance of FLDL, MLDL, EMLDL, and SLDL with DLDL in TG values ranging from 200 to 799 mg/dL were 52.2, 70.5, 71.6, and 65.7%, respectively (p < 0.001), demonstrating the EMLDL as the most optimal estimation method, particularly for high TG levels (≥200 mg/dL). CONCLUSION: Both the original and extended Martin/Hopkins method are optimal in estimating LDL-C levels in clinical laboratories using the Abbott analyzer in patients with TG levels of 200-399 and 400-799 mg/dL, respectively. Meanwhile, caution is need that considerable underestimation of Friedewald and Sampson equation could lead to undertreatment in hypertriglyceridemia.

An increase in calculated small dense low-density lipoprotein cholesterol predicts new onset of hypertension in a Japanese cohort.

A disorder of lipid metabolism is involved in cardiovascular diseases including hypertension. A high level of small dense low-density lipoprotein cholesterol (sdLDL-C) is a strong risk factor for atherosclerotic cardiovascular disease. However, the association between sdLDL-C and hypertension has not been fully investigated. We investigated the associations between the development of hypertension during a 10-year period and levels of total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), non-HDL-C, triglycerides (TG), and LDL-C and sdLDL-C calculated by using the Sampson equations in 28,990 Japanese subjects who received annual health examinations. After exclusion of subjects with missing data, those with hypertension, and those with TG ≥ 800 mg/dL at baseline, a total of 15,177 subjects (men/women: 9374/5803, mean age: 46 years) were recruited. During the 10-year period, 2379 men (25.4%) and 724 women (12.5%) had new onset of hypertension. Multivariable Cox proportional hazard model analyses showed that levels of HDL-C, non-HDL-C, TG and sdLDL-C, but not levels of TC and LDL-C, were independent risk factors for the development of hypertension after adjustment of age, sex, family history of hypertension, systolic blood pressure, obesity, current smoking habit, alcohol drinking habit, estimated glomerular filtration rate, diagnosis of diabetes mellitus and use of lipid-lowering drugs and that the adjusted risk of sdLDL-C (per 1-standard deviation) was highest (hazard ratio [95% confidence interval: 1.09 [1.05-1.13]). The addition of sdLDL-C to traditional risk factors for hypertension significantly improved the discriminatory capability, which was better than that of other lipid fractions. In conclusion, a high level of calculated sdLDL-C predicts the development of hypertension.

Measurement of Serum Low Density Lipoprotein Cholesterol and Triglyceride-Rich Remnant Cholesterol as Independent Predictors of Atherosclerotic Cardiovascular Disease: Possibilities and Limitations.

The serum low density lipoprotein cholesterol (LDL-C) concentration is the dominant clinical parameter to judge a patient's risk of developing cardiovascular disease (CVD). Recent evidence supports the theory that cholesterol in serum triglyceride-rich lipoproteins (TRLs) contributes significantly to the atherogenic risk, independent of LDL-C. Therefore, combined analysis of both targets and adequate treatment may improve prevention of CVD. The validity of TRL-C calculation is solely dependent on the accuracy of the LDL-C measurement. Direct measurement of serum LDL- C is more accurate than established estimation procedures based upon Friedewald, Martin-Hopkins, or Sampson equations. TRL-C can be easily calculated as total C minus high density lipoprotein C (HDL-C) minus LDL-C. Enhanced serum LDL-C or TRL-C concentrations require different therapeutic approaches to lower the atherogenic lipoprotein C. This review describes the different atherogenic lipoproteins and their possible analytical properties and limitations.

Comparison of low-density lipoprotein cholesterol estimation methods in individuals with insulin resistance: A cross-sectional study.

BACKGROUND AND AIMS: The Friedewald, Sampson, and Martin equations were developed to estimate low-density lipoprotein cholesterol levels; however, the validation data of these equations with and without insulin resistance are insufficient. MATERIALS AND METHODS: We collected data on low-density lipoprotein cholesterol and lipid profiles from the Korea National Health and Nutrition Examination Survey. Using the data on insulin requirement, insulin resistance was calculated for 4,351 participants (median age, 48 [36-59] years; 49.9% male) using the homeostatic model assessment for insulin resistance (n = 2,713) and quantitative insulin-sensitivity check index (n = 2,400). RESULTS: According to the mean and median absolute deviation, the Martin equation yielded more accurate estimates than other equations when the triglyceride level was < 400 mg/dL with insulin resistance; the Sampson equation yielded lower estimates when the direct low-density lipoprotein cholesterol level was < 70 mg/dL and triglyceride level was < 400 mg/dL without insulin resistance. However, the three equations yielded similar estimates when the triglyceride level was < 150 mg/dL with and without insulin resistance. CONCLUSION: The Martin equation yielded more appropriate estimates than the Friedewald and Sampson equations for triglyceride levels < 400 mg/dL with and without insulin resistance. If the triglyceride level was < 150 mg, the Friedewald equation could also be considered.

Comparison of the accuracy of the Friedewald, Martin, and Sampson formulas to estimate very low levels of low-density lipoprotein cholesterol.

INTRODUCTION: The Martin (MF) and Sampson (SF) formulas have shown greater accuracy for low-density lipoprotein cholesterol (LDL-C) < 70 mg/dL compared to the Friedewald formula (FF); however, some disagreement is maintained. Non-high-density lipoprotein cholesterol (non-HDL-C) and apolipoprotein B (ApoB) are alternatives to assessing cardiovascular risk in patients with very low LDL-C. The objective was to evaluate the accuracy of FF, MF, and SF formulas to estimate LDL-C < 70 mg/dL vs. directly measured LDL-C (LDLd-C) and to compare non-HDL-C and Apo-B levels between the groups of patients with concordant vs. discordant LDL-C. MATERIAL AND METHODS: This was a prospective clinical study with measurements of lipid profile and LDLd-C in 214 patients with triglycerides < 400 mg/dL. For each formula, the estimated LDL-C was compared with the LDLd-C, and the correlation, the median difference, and the discordance rate were evaluated. Non-HDL-C and Apo-B levels were compared between the groups with concordant and discordant LDL-C. RESULTS: The estimated LDL-C was < 70 mg/dL in 130 (60.7%) patients by FF, 109 (50.9%) by MF, and 113 (52.8%) by SF. The strongest correlation was found between LDLd-C and Sampson estimated LDL-C (LDLs-C) (R2 = 0.778), followed by Friedewald-estimated LDL-C (LDLf-C) (R2 = 0.680) and Martin estimated LDL-C (LDLm-C) (R2 = 0.652). Estimated LDL-C < 70 mg/dL was lower than LDLd-C, with the largest median absolute difference (25-75th) of -15 (-19 to -10) with FF. For estimated LDL-C < 70 mg/dL, the discordant rate was 43.8%, 38.1%, and 35.1%, reaching for 62.3%, 50.9%, and 50% when LDL-C < 55 mg/dL by FF, SF, and MF, respectively. Patients in the discordant group presented significantly higher levels of non-HDL-C and ApoB for all 3 formulas (p < 0.001). CONCLUSION: FF was the most inaccurate formula to estimate very low LDL-C. Despite MF and SF showing better results, their frequency in underestimating LDL-C was still considerable. In patients with falsely low estimated LDL-C, apoB and non-HDL-C were significantly higher, reflecting its true high atherogenic burden.

Performance of equations for calculated LDL-C in hypertriglyceridaemia: Which one correlates best with directly measured LDL-C?

BACKGROUND: The gold standard for measuring LDL-C is impractical and direct measurements have numerous shortcomings. Older predictive equations are used only with triglycerides (TG's) below 4.52 mmol/L. We evaluated the newer equations validated for use in hypertriglyceridaemia by comparison with direct LDL-C. MATERIALS AND METHODS: Datasets from two platforms (Abbott Architect and Roche Cobas) comprised of a large cohort of 64,765 individuals were used to compare the Sampson-National Institutes of Health 2 (S-NIH2) and Extended Martin-Hopkins (E-MH) equations for LDL-C with direct LDL-C (dLDL-C) assays. RESULTS: With TG's of 4.52-9.04 mmol/L the S-NIH2 equation tended to calculate lower values than measured by dLDL-C and the E-MH equation calculated higher values. Both equations correlated better with the dLDL-C measured on Abbott than Roche with the E-MH equation having more values falling within acceptable concordance levels on both platforms. CONCLUSION: The E-MH equation correlates better with dLDL-C than the S-NIH2 on both platforms with TG levels up to 9.04 mmol/L. With hypertriglyceridaemia, the E-MH equation is less likely than the S-NIH2 equation to underestimate LDL-C when compared to the dLDL-C and will be less likely to underdiagnose patients with LDL-C levels requiring treatment according to current guidelines.

Evaluation of low-density lipoprotein cholesterol equations by cross-platform assessment of accuracy-based EQA data against SI-traceable reference value.

OBJECTIVES: Low-density lipoprotein cholesterol (LDLC) is the primary cholesterol target for the diagnosis and treatment of cardiovascular disease (CVD). Although beta-quantitation (BQ) is the gold standard to determine LDLC levels accurately, many clinical laboratories apply the Friedewald equation to calculate LDLC. As LDLC is an important risk factor for CVD, we evaluated the accuracy of Friedewald and alternative equations (Martin/Hopkins and Sampson) for LDLC. METHODS: We calculated LDLC based on three equations (Friedewald, Martin/Hopkins and Sampson) using the total cholesterol (TC), triglycerides (TG), and high-density lipoprotein cholesterol (HDLC) in commutable serum samples measured by clinical laboratories participating in the Health Sciences Authority (HSA) external quality assessment (EQA) programme over a 5 years period (number of datasets, n=345). LDLC calculated from the equations were comparatively evaluated against the reference values, determined from BQ-isotope dilution mass spectrometry (IDMS) with traceability to the International System of Units (SI). RESULTS: Among the three equations, Martin/Hopkins equation derived LDLC had the best linearity against direct measured (y=1.141x - 14.403; R2=0.8626) and traceable LDLC (y=1.1692x - 22.137; R2=0.9638). Martin/Hopkins equation (R2=0.9638) had the strongest R2 in association with traceable LDLC compared with the Friedewald (R2=0.9262) and Sampson (R2=0.9447) equation. The discordance with traceable LDLC was the lowest in Martin/Hopkins (median=-0.725%, IQR=6.914%) as compared to Friedewald (median=-4.094%, IQR=10.305%) and Sampson equation (median=-1.389%, IQR=9.972%). Martin/Hopkins was found to result in the lowest number of misclassifications, whereas Friedewald had the most numbers of misclassification. Samples with high TG, low HDLC and high LDLC had no misclassification by Martin/Hopkins equation, but Friedewald equation resulted in ∼50% misclassification in these samples. CONCLUSIONS: The Martin/Hopkins equation was found to achieve better agreement with the LDLC reference values as compared to Friedewald and Sampson equations, especially in samples with high TG and low HDLC. Martin/Hopkins derived LDLC also enabled a more accurate classification of LDLC levels.

Comparison of low-density lipoprotein cholesterol equations in patients with dyslipidaemia receiving cholesterol ester transfer protein inhibition.

AIMS: Low-density lipoprotein (LDL-C) lowering is imperative in cardiovascular disease prevention. We aimed to compare accuracy of three clinically-implemented LDL-C equations in a clinical trial of cholesterol ester transfer protein (CETP) inhibition. METHODS AND RESULTS: Men and women aged 18-75 years with dyslipidaemia were recruited from 17 sites in the Netherlands and Denmark. Patients were randomly assigned to one of nine groups using various combinations of the CETP inhibitor TA-8995 (obicetrapib), statin therapy, and placebo. In pooled measurements over 12 weeks, we calculated LDL-C by the Friedewald, Martin/Hopkins, and Sampson equations, and compared values with preparative ultracentrifugation (PUC) LDL-C overall and with a special interest in the low LDL-C/high triglycerides subgroup. There were 242 patients contributing 921 observations. Overall median LDL-C differences between estimates and PUC were small: Friedewald, 0.00 (25th, 75th: -0.10, 0.08) mmol/L [0 (-4, 3) mg/dL]; Martin/Hopkins, 0.02 (-0.08, 0.10) mmol/L [1 (-3, 4) mg/dL]; and Sampson, 0.05 (-0.03, 0.15) mmol/L [2 (-1, 6) mg/dL]. In the subgroup with estimated LDL-C <1.8 mmol/L (<70 mg/dL) and triglycerides 1.7-4.5 mmol/L (150-399 mg/dL), the Friedewald equation underestimated LDL-C with a median difference versus PUC of -0.25 (-0.33, -0.10) mmol/L [-10 (-13, -4) mg/dL], whereas the median difference by Martin/Hopkins was 0.00 (-0.08, 0.10) mmol/L [0 (-3, 4) mg/dL] and by Sampson was -0.06 (-0.13, 0.00) mmol/L [-2 (-5, 0) mg/dL]. In this subgroup, the proportion of LDL-C observations <1.8 mmol/L (<70 mg/dL) that were correctly classified compared with PUC was 71.4% by Friedewald vs. 100.0% by Martin/Hopkins and 93.1% by Sampson. CONCLUSION: In European patients with dyslipidaemia receiving a CETP inhibitor, we found improved LDL-C accuracy using contemporary equations vs. the Friedewald equation, and the greatest accuracy was observed with the Martin/Hopkins equation. REGISTRATION: ClinicalTrials.gov, NCT01970215.

Accuracy of Small Dense Low-density Lipoprotein-cholesterol Concentration Estimated via Sampson's Equation in Healthy Subjects and Patients with Diabetes.

AIM: Sampson et al. proposed a method to calculate small dense low-density lipoprotein-cholesterol (sdLDL-C) concentrations using common lipid measurements, but its accuracy remains unresolved. We examined the difference between Sampson's equation and direct measurement in patients with diabetes. METHODS: sdLDL-C was measured directly by our established homogeneous assay and estimated by Sampson's equation in patients with diabetes (n=1542) and healthy control subjects (n=673). Large-buoyant (lb)LDL-C was estimated using triglycerides and LDL-C, and sdLDL-C was obtained by subtracting lbLDL-C from LDL-C. The effect of fasting/nonfasting state or lipid-lowering drug therapy on sdLDL-C values was also examined in 30 and 43 patients with diabetes, respectively. RESULTS: The coefficient of determination (R2) between calculated sdLDL-C and direct measurement was 0.73 and 0.61 for healthy controls and patients with diabetes, respectively. The R2 between calculated sdLDL-C and nonHDL-C or apolipoprotein B was 0.64 and 0.65, respectively. Calculated sdLDL-C was 4-5 mg/dl or 17%-18% higher than the direct measurement. The lower the plasma lipids, especially sdLDL-C, the greater the dissociation between the two methods. Sampson sdLDL-C was also found to give a positive bias when calculated for the nonfasting samples. Statins and pemafibrate significantly reduced sdLDL-C, but their therapeutic effect was underestimated by 5 mg/dl (24%) via Sampson's equation. CONCLUSIONS: The correlation between Sampson's equation and direct measurements of sdLDL-C was reduced in patients with diabetes. Furthermore, the correlations with nonHDL-C and apolipoprotein B were even higher than those with direct sdLDL-C. The accuracy of Sampson's equation decreased with lower sdLDL-C concentrations and was also influenced by diet.

Comparability of calculated LDL-C with directly measured LDL-C in selected paediatric and adult cohorts.

BACKGROUND AND AIMS: The gold standard for measuring LDL-C is impractical for routine use while direct measurements have numerous shortcomings. This study investigated the correlation of predictive equations with currently used enzymatic assays in populations where these have historically proven unreliable to determine whether equations may be used interchangeably. No reference measure was available for comparison in this study. MATERIALS AND METHODS: We examined two analytical datasets from different platforms to evaluate the correlation of predictive equations for LDL-C (Friedewald, Sampson-NIH2, Martin-Hopkins, Extended Martin-Hopkins, Hattori and Anandaraja) with direct LDL-C assays in a large paediatric (n = 7598) and an adult cohort with uncontrolled diabetes (n = 57165). Non-parametric statistics were used for comparison. RESULTS: In the paediatric cohort, the Sampson-NIH2 equation correlated best with the direct LDL-C assays with the most values falling within desirable bias (35.9-44%) and TEa (68.6-72.9%) and the lowest RMSE (0.5904-0.6138) across platforms, but tended to underestimate LDL-C levels. The Martin-Hopkins equation is less likely to underestimate these values. In diabetes, the Martin-Hopkins equation correlated the best with values falling within acceptable bias (40.2-50.5%) and TEa (75-80.6%). In hypertriglyceridaemia the Extended Martin-Hopkins equation correlates best with the direct LDL-C assays. CONCLUSION: Different measurement platforms influence the results of predictive equations and directly measured LDL-C. We propose utilising the Martin-Hopkins equation as an alternative to dLDL-C assays in adults with diabetes and for screening purposes in paediatric populations to avoid underestimating cardiovascular risk.