Figure 1
Diagram of Primary and Secondary Testing to Select the Highest Performing Equation. The figure shows the sequence of analysis, first comparing all 23 equations against ultracentrifugation for concordance in guideline-based LDL-C classification and overall magnitude of error (mg/dL units). In secondary testing, we compared Friedewald and the five equations that performed better than Friedewald in primary testing. These secondary tests evaluated performance at different levels of elevated triglycerides, by age (<18, 18–59, >60 years), sex, and fasting status strata, and across clinical subgroups (ASCVD, DM, HTN, CKD, abnormal TSH, high hsCRP). Finally, we assessed the top performing equation (Martin/Hopkins) for its impact in classification across an important clinical cutpoint in high risk patients (LDL-C 70 mg/dL) if a laboratory were to switch from the Friedewald equation. Patients highlighted in orange are ones with Friedewald LDL-C<70 mg/dL who have correct (confirmed by ultracentrifugation) upward reclassification to LDL-C >70 mg/dL by Martin-Hopkins. Patients highlighted in blue remain classified as LDL-C <70 mg/dL by both equations. Abbreviations: TGs = triglycerides; ASCVD = atherosclerotic cardiovascular disease; DM = diabetes mellitus; HTN = hypertension; CKD = chronic kidney disease; TSH = thyroid stimulating hormone; hsCRP = high-sensitivity C-reactive protein; LDL-C = low-density lipoprotein cholesterol.
Table 1
Demographic characteristics.
| CHARACTERISTICS | STUDY POPULATION (N = 4,939,528) |
|---|---|
| Age, mean (SD), y | 56 (16) |
| Age category, no. (%), y | |
| <18 | 59,838 (1.2) |
| 18–59 | 2,879,747 (58.3) |
| ≥60 | 1,966,468 (39.8) |
| Not reported | 33,475 (0.7) |
| Sex, no. (%) | |
| Women | 2,635,486 (53.7) |
| Men | 2,269,406 (46.3) |
| Fasting status, no. (%) | |
| Non-fasting | 586,256 (11.9) |
| Fasting | 958,989 (19.4) |
| Not reported | 3,394,283 (68.7) |
| Lipid values, median (IQR) | |
| TC, mg/dL | 193 (164–225) |
| TG, mg/dL | 114 (81–164) |
| HDL-C, mg/dL | 51 (42–63) |
| LDL-C, mg/dL (ultracentrifugation) | 114 (90–141) |
| Non-HDL-C, mg/dL | 138 (112–168) |
| VLDL-C, mg/dL | 22 (17–29) |
| Lp(a)-C, mg/dL | 6 (4–10) |
| TC:VLDL-C ratio | 8.4 (6.5–10.9) |
| TG:VLDL-C ratio | 5.0 (4.4–5.9) |
| TG:TC ratio | 0.6 (0.4–0.9) |
[i] IQR = interquartile range; TC = total cholesterol; HDL-C = high-density lipoprotein cholesterol; LDL-C = low-density lipoprotein cholesterol; VLDL-C = very low-density lipoprotein cholesterol; Lp(a)-C = lipoprotein(a) cholesterol.
Table 2
Percentage of patients correctly classified to LDL-C category.
| EQUATION | LDL-C CATEGORY, MG/DL | ||||||||
|---|---|---|---|---|---|---|---|---|---|
| <40 | 40–54 | 55–69 | 70–99 | 100–129 | 130–159 | 160–189 | ≥190 | OVERALL | |
| Martin/Hopkins | 78.6 | 81.2 | 84.2 | 91.7 | 90.8 | 89.2 | 86.6 | 91.1 | 89.6 |
| Sampson | 66.0 | 71.8 | 77.8 | 90.5 | 89.0 | 85.4 | 80.5 | 84.4 | 86.3 |
| Chen | 85.9 | 81.1 | 80.2 | 86.0 | 84.3 | 83.2 | 81.7 | 95.7 | 84.4 |
| Puavilai | 62.5 | 69.7 | 75.0 | 89.3 | 87.2 | 83.1 | 77.0 | 79.2 | 84.1 |
| DeLong | 66.8 | 72.3 | 76.2 | 89.6 | 86.4 | 81.4 | 74.4 | 76.8 | 83.3 |
| Friedewald | 42.1 | 52.5 | 62.6 | 83.8 | 87.0 | 87.7 | 86.1 | 90.0 | 83.2 |
| Molavi | 44.6 | 54.2 | 63.0 | 82.8 | 85.6 | 87.2 | 87.6 | 95.2 | 82.9 |
| Saiedullah | 72.2 | 65.8 | 66.0 | 81.1 | 83.6 | 85.8 | 86.6 | 95.4 | 82.1 |
| Vujovic | 75.7 | 76.3 | 77.0 | 89.2 | 83.6 | 76.6 | 68.0 | 71.2 | 80.3 |
| Teerakanchana | 83.5 | 70.8 | 67.0 | 83.8 | 78.4 | 76.6 | 75.7 | 83.8 | 78.5 |
| Orejon | 71.5 | 67.8 | 68.0 | 85.3 | 80.4 | 76.1 | 71.1 | 76.4 | 78.5 |
| Dansethakul | 52.1 | 58.1 | 62.1 | 82.7 | 77.9 | 72.9 | 67.1 | 73.3 | 75.2 |
| Bauer | 87.2 | 77.6 | 73.6 | 86.5 | 77.5 | 68.3 | 57.8 | 63.2 | 73.8 |
| Rao | 42.3 | 54.2 | 61.8 | 82.7 | 76.4 | 67.3 | 56.4 | 62.7 | 71.0 |
| Ghasemi | 21.6 | 28.9 | 38.8 | 68.0 | 75.5 | 80.5 | 83.3 | 97.8 | 69.1 |
| Ephraim | 93.0 | 74.3 | 67.0 | 83.0 | 71.7 | 61.1 | 49.8 | 57.3 | 67.5 |
| Hattori | 33.9 | 38.1 | 43.5 | 67.7 | 70.9 | 73.1 | 73.9 | 99.1 | 67.0 |
| Lee and Hu | 81.4 | 63.4 | 57.8 | 74.0 | 66.0 | 63.4 | 61.5 | 81.9 | 66.9 |
| Rasouli | 74.9 | 65.4 | 62.3 | 68.1 | 59.8 | 48.6 | 29.0 | 99.5 | 60.3 |
| Cordova | 86.8 | 64.5 | 54.6 | 62.6 | 56.6 | 50.1 | 41.1 | 96.7 | 57.5 |
| Anandaraja | 29.9 | 36.0 | 43.3 | 67.6 | 59.4 | 52.1 | 45.3 | 56.5 | 55.9 |
| Choi | 88.3 | 56.1 | 44.4 | 73.0 | 57.9 | 46.7 | 36.2 | 49.2 | 53.4 |
| Ahmadi | 27.5 | 26.0 | 31.8 | 58.7 | 49.1 | 34.8 | 18.8 | 16.5 | 35.1 |
Table 3
Error between estimated LDL-C and VAP ultracentrifugation LDL-C.
| EQUATION | ERROR, MEDIAN (IQR), MG/DL | RELATIVE ERROR, MEDIAN (IQR), % |
|---|---|---|
| Friedewald | –0.2 (–4.4 to 2.6) | –0.2 (–4.0 to 2.2) |
| Martin/Hopkins | 0.3 (–1.6 to 2.4) | 0.2 (–1.4 to 2.1) |
| Sampson | 1.7 (–1.3 to 4.1) | 1.6 (–1.2 to 3.5) |
| Puavilai | 3.3 (0.5 to 5.5) | 2.9 (0.4 to 4.9) |
| Vujovic | 5.5 (3.2 to 7.7) | 4.8 (2.8 to 6.9) |
| Hattori | –7.6 (–11.8 to –4.6) | –6.4 (–10.0 to –4.1) |
| Anandaraja | 5.9 (–4.3 to 17.5) | 5.1 (–3.6 to 16.1) |
| Chen | –2.9 (–5.6 to –0.2) | –2.6 (–4.4 to –0.3) |
| Cordova | –10.8 (–17.2 to –4.5) | –9.8 (–13.4 to –4.7) |
| Teerakanchana | 5.2 (1.7 to 8.9) | 4.6 (1.3 to 8.7) |
| Ahmadi | 18.7 (–2.6 to 50.6) | 16.4 (–2.3 to 44.6) |
| DeLong | 4.1 (1.4 to 6.2) | 3.5 (1.2 to 5.5) |
| Rao | 7.7 (2.3 to 11.6) | 6.8 (2.1 to 9.9) |
| Ephraim | 9.4 (7.3 to 12.2) | 8.4 (6.4 to 11.1) |
| Saiedullah | –3.9 (–6.0 to –1.5) | –3.4 (–5.3 to –1.3) |
| Dansethakul | 6.9 (2.7 to 9.7) | 5.8 (2.2 to 8.8) |
| Rasouli | –10.1 (–16.6 to –4.0) | –8.8 (–12.3 to –4.3) |
| Ghasemi | –5.8 (–12.0 to –1.8) | –5.1 (–11.0 to –1.6) |
| Lee and Hu | 3.8 (–3.8 to 12.0) | 3.4 (–3.0 to 12.0) |
| Orejon | 6.2 (3.4 to 8.3) | 5.3 (2.7 to 8.0) |
| Bauer | 7.6 (5.6 to 10.1) | 6.8 (4.9 to 9.1) |
| Molavi | –1.1 (–5.2 to 1.7) | –0.9 (–4.5 to 1.5) |
| Choi | 14.5 (11.8 to 17.2) | 12.6 (9.8 to 16.0) |
Figure 2
Upward Reclassification of Patients with Friedewald LDL-C < 70 mg/dL When Using an Alternative LDL-C Equation. The figure displays the percentage of patients with Friedewald LDL-C < 70 mg/dL who are reclassified to LDL-C > 70 mg/dL by top performing equations and confirmed to have a correct reclassification by ultracentrifugation. Reclassification for patients with TG levels of <400 mg/dL (n = 539,575) is highlighted in blue and for patients with TG levels of 150–399 mg/dL (n = 183,455) is highlighted in dark blue. Abbreviations: LDL-C = low-density lipoprotein cholesterol; TG = triglyceride.