Summary of statistical results for various options of the clinical diagnostic pathway and various combinations of variables
| Option of clinical pathway . | Variables included . | No. of criteria∗ . | AUC† . | Accuracy . | Sensitivity . | Specificity . | PPV . | NPV . |
|---|---|---|---|---|---|---|---|---|
| No. of diagnostic criteria fulfilled | Exact values based on current optimization‡ | 4/7 | 0.9976 | 97.7% | 98.1% | 97.6% | 89.1% | 99.6% |
| Exact values as above + fever + sCD25§ | 6/9 | 0.9991 | 99.1% | 97.1% | 99.5% | 97.6% | 99.4% | |
| Rounded values (ferritin ≥500 μg/L)|| | 5/9 | 0.9961 | 99.1% | 97.1% | 99.5% | 97.6% | 99.4% | |
| Rounded values (ferritin ≥1000 μg/L)|| | 5/9 | 0.9967 | 99.1% | 97.1% | 99.5% | 97.6% | 99.4% | |
| HLH-2004 criteria | Current criteria¶ | 5/8 | 0.9920 | 97.4% | 99.0% | 97.1% | 87.3% | 99.8% |
| Current criteria except NK-cell activity¶ | 5/7 | 0.9924 | 99.0% | 96.2% | 99.5% | 97.6% | 99.2% | |
| Ferritin ≥500 μg/L, sCD25 ≥2400 U/mL | 4/7 | 0.9924 | 93.8% | 99.0% | 92.8% | 73.3% | 99.8% | |
| Ferritin ≥1000 μg/L, sCD25 ≥2400 U/mL | 5/7 | 0.9932 | 99.4% | 96.2% | 100% | 100% | 99.2% | |
| Ferritin ≥1000 μg/L, sCD25 ≥2400 U/mL | 4/7 | 0.9932 | 94.6% | 99.0% | 93.8% | 76.0% | 99.8% | |
| Ferritin ≥500 μg/L, sCD25 ≥5000 U/mL | 5/7 | 0.9951 | 96.2% | 96.2% | 100% | 100% | 99.2% | |
| Ferritin ≥500 μg/L, sCD25 ≥5000 U/mL | 4/7 | 0.9951 | 98.2% | 99.0% | 98.1% | 91.2% | 99.8% | |
| Ferritin ≥1000 μg/L, sCD25 ≥5000 U/mL | 5/7 | 0.9954 | 99.4% | 96.2% | 100% | 100% | 99.2% | |
| Ferritin ≥1000 μg/L, sCD25 ≥5000 U/mL | 4/7 | 0.9954 | 99.1% | 99.0% | 99.0% | 95.4% | 99.8% | |
| Numerical score using cutoffs for continuous laboratory values | At score 115, FHL probability was 56.2%. Variables: splenomegaly, neutrophils, platelets, triglycerides, fibrinogen, ferritin, and bilirubin | 0.9980 | 98.5% | 98.1% | 98.6% | 93.2% | 99.6% | |
| Numerical score using a continuous scale for laboratory values | Variables: splenomegaly, hepatomegaly, hemoglobin, neutrophils, platelets, triglycerides, fibrinogen, ferritin, ALT, LDH, and bilirubin | 0.9976 | NA | NA | NA | NA | NA |
| Option of clinical pathway . | Variables included . | No. of criteria∗ . | AUC† . | Accuracy . | Sensitivity . | Specificity . | PPV . | NPV . |
|---|---|---|---|---|---|---|---|---|
| No. of diagnostic criteria fulfilled | Exact values based on current optimization‡ | 4/7 | 0.9976 | 97.7% | 98.1% | 97.6% | 89.1% | 99.6% |
| Exact values as above + fever + sCD25§ | 6/9 | 0.9991 | 99.1% | 97.1% | 99.5% | 97.6% | 99.4% | |
| Rounded values (ferritin ≥500 μg/L)|| | 5/9 | 0.9961 | 99.1% | 97.1% | 99.5% | 97.6% | 99.4% | |
| Rounded values (ferritin ≥1000 μg/L)|| | 5/9 | 0.9967 | 99.1% | 97.1% | 99.5% | 97.6% | 99.4% | |
| HLH-2004 criteria | Current criteria¶ | 5/8 | 0.9920 | 97.4% | 99.0% | 97.1% | 87.3% | 99.8% |
| Current criteria except NK-cell activity¶ | 5/7 | 0.9924 | 99.0% | 96.2% | 99.5% | 97.6% | 99.2% | |
| Ferritin ≥500 μg/L, sCD25 ≥2400 U/mL | 4/7 | 0.9924 | 93.8% | 99.0% | 92.8% | 73.3% | 99.8% | |
| Ferritin ≥1000 μg/L, sCD25 ≥2400 U/mL | 5/7 | 0.9932 | 99.4% | 96.2% | 100% | 100% | 99.2% | |
| Ferritin ≥1000 μg/L, sCD25 ≥2400 U/mL | 4/7 | 0.9932 | 94.6% | 99.0% | 93.8% | 76.0% | 99.8% | |
| Ferritin ≥500 μg/L, sCD25 ≥5000 U/mL | 5/7 | 0.9951 | 96.2% | 96.2% | 100% | 100% | 99.2% | |
| Ferritin ≥500 μg/L, sCD25 ≥5000 U/mL | 4/7 | 0.9951 | 98.2% | 99.0% | 98.1% | 91.2% | 99.8% | |
| Ferritin ≥1000 μg/L, sCD25 ≥5000 U/mL | 5/7 | 0.9954 | 99.4% | 96.2% | 100% | 100% | 99.2% | |
| Ferritin ≥1000 μg/L, sCD25 ≥5000 U/mL | 4/7 | 0.9954 | 99.1% | 99.0% | 99.0% | 95.4% | 99.8% | |
| Numerical score using cutoffs for continuous laboratory values | At score 115, FHL probability was 56.2%. Variables: splenomegaly, neutrophils, platelets, triglycerides, fibrinogen, ferritin, and bilirubin | 0.9980 | 98.5% | 98.1% | 98.6% | 93.2% | 99.6% | |
| Numerical score using a continuous scale for laboratory values | Variables: splenomegaly, hepatomegaly, hemoglobin, neutrophils, platelets, triglycerides, fibrinogen, ferritin, ALT, LDH, and bilirubin | 0.9976 | NA | NA | NA | NA | NA |
A prevalence of FHL of 16% in the study population was assumed, that is, similar as in the Italian HLH Registry.
ALT, alanine transaminase; NA, not applicable.
The number of criteria presented here are the numbers that maximizes the sensitivity and specificity.
AUC is calculated based on all criteria and not just 5 of 7 criteria, or similar.
Splenomegaly, neutrophils ≤2.7 × 109/L, platelets ≤136 × 109/L, triglycerides ≥2.08 mmol/L, fibrinogen ≤2.6 g/L, ferritin ≥621 μg/L, and bilirubin ≥17 μmol/L.
As above, as well as fever and sCD25 ≥5369 U/mL.
Fever, splenomegaly, neutrophils ≤1.0 × 109/L, platelets ≤100 × 109/L, triglycerides ≥2.0 mmol/L, fibrinogen ≤2.5 g/L, ferritin ≥500 μg/L or 1000 μg/L, sCD25 ≥5000 U/mL, and bilirubin ≥20 μmol/L.
Ferritin, ≥500 μg/L and sCD25, ≥2400 U/mL.