Journal of Neurology (JOON-D-10-00389)

Utility of measuring vitamin B12 and its active fraction, holotranscobalamin, in neurological vitamin B12 deficiency syndromes

Wiebke Schrempf, MDa; Marco Eulitza; Volker Neumeister, Chem-Db; Gabriele Siegert, PhDb; Rainer Koch, PhDc, Heinz Reichmann, PhDa; Alexander Storch, MDa,*

Supplementary Tables

Supplementary Table S1: Neurological diagnosis / indications for measuring VitB12 metabolism parametersa

Neurological diagnosis / Indication / All (N [%]) / Normal renal functions cohort (N [%]) / Abnormal renal functions cohort (N [%])
Peripheral neuropathy / 925 (72.3%) / 591 (69.4%) / 228 (79.2%)
Subacute combined degeneration / 76 (5.9%) / 58 (6.8%) / 12 (4.2%)
Cognitive disorder / impairment / 107 (8.4) / 82 (9.6%) / 25 (8.7%)
Various / 171 (13.4%) / 120 (14.1%) / 23 (8.0%)
Multiple Sclerosis / 55 (4.3%) / 41 (4.8%) / 1 (0.3%)
Restless-legs Syndrome (RLS) / 38 (3%) / 25 (2.9%) / 9 (3.1%)
Movement Disorders / 38 (3%) / 26 (3.1%) / 7 (2.4%)
Motoneuron Diseases / 34 (2.6%) / 24 (2.8%) / 3 (1.1%)
Various / 6 (0.5) / 4 (0.5%) / 3 (1.1%)
Total / 1279 (100%) / 851 (100%) / 288 (100%)

a In the case the subject suffered from more than one diagnosis, the indication for measuring VitB12 parameters is indicated.

Supplementary Table S2: Comparison of the utility of vitamin B12 and holoTC for detection of vitamin B12 deficiency (MMA > 47 µg/l) in the overall patient cohort using cut-off values from the ROC analysis, the cut-off values from the manufacturer, and the cut-off values with 95% sensitivity

Total vitamin B12 / holoTC
ROC analysis cut-off (< 280 pg/ml) / Manufacturer cut-off (< 211 pg/ml) / 95% sensitivity cut-off (< 630 pg/ml) / ROC analysis cut-off (< 42 pmol/l) / Manufacturer cut-off (< 19 pmol/l) / 95% sensitivity cut-off (< 77 pmol/l)
Sensitivity (a/(a+b)), n (%) [95%CI] / 70/111 (63.1%) [54.1-72.1] / 38/111 (34.2%) [25.6-43.0] / 105/111 (94.6%) [90.4-98.8] / 11/24 (45.8%) [25.9-65.7] / 1/24 (4.2%) [0.0-12.2] / 23/24 (95.8%) [87.8-100.0]
Specificity (d/(c+d)), n (%) [95%CI] / 407/632 (64.4%) [62.7-68.1] / 555/632 (87.8%) [85.2-90.4] / 59/632 (9.3%) [7.0-11.6] / 76/143 (53.1%) [44.9-61.3] / 143/147 (97.3%) [91.5-99.90] / 13/142 (9.2%) [4.5-13.7]
Positive predictive valuea, % / 23.5% / 32.7% / 15.3% / 14.5% / 21.3% / 15.5%
Negative predictive valuea, % / 90.9% / 88.5% / 90.8% / 84.9% / 85.4% / 92.7%
Likelihood ratio ([a/(a+b)]/[c/(c+d]) / 1.8 / 2.8 / 1.0 / 1.0 / 1.5 / 1.1

a Calculated using the Bayes' theorem.


Supplementary Table S3: Comparison of the utility of vitamin B12 and holoTC for detection of vitamin B12 deficiency (MMA > 47 µg/l) using cut-off values from the manufacturera,b

Total vitamin B12 / holoTC
All / Classical VitB12 deficiency syndromesc / Peripheral neuropathy, / All / Classical VitB12 deficiency syndromesc / Peripheral neuropathy
Sensitivity (a/(a+b)), n (%) [95%CI] / 27/71 (38.0%) [26.7-49.3] / 22/61 (36.1%) [24.0-48.2] / 21/54 (38.9%) [25.9-51.9] / 1/16 (6.3%) [0.0-18.2] / 1/16 (6.3%) [0.0-18.2] / 1/15 (6.7%) [0.0-19.4]
Specificity (d/(c+d)), n (%) [95%CI] / 401/462 (86.8%) [83.7-89.9] / 294/342 (86.0%) [82.3-89.7] / 257/301 (85.4%) [81.41-89.4] / 106/109 (97.2%) [94.1-100.0] / 89/90 (98.9%) [96.7-100.0] / 85/88 (96.6%) [92.8-100.0]
Positive predictive valued, % / 30.4% / 31.4% / 32.2% / 25.5% / 25.8% / 26.0%
Negative predictive valued, % / 90.2% / 88.3% / 88.7% / 87.2% / 85.6% / 85.3%
Likelihood ratio ([a/(a+b)]/[c/(c+d]) / 2.9 / 2.6 / 2.7 / 2.2 / 2.7 / 2.0

a Total vitamin B12 serum level < 211 pg/ml; serum holoTC level < 19 pmol/l.

b Only subjects with normal renal function as defined as ≤ 106µg/l (males), ≤ 80 µmol/l (female) were included into the analyses

c Subcohort of subjects with peripheral neuropathy and/or subacute combined degeneration

d Calculated using the Bayes' theorem.

Supplementary Table S4: Comparison of the utility of vitamin B12 and holoTC for detection of vitamin B12 deficiency (MMA > 47 µg/l) using cut-off values with 95% sensitivitya,b

Total vitamin B12 / holoTC
All) / Classical VitB12 deficiency syndromesc / Peripheral neuropathy / All / Classical VitB12 deficiency syndromesc / Peripheral neuropathy
Sensitivity (a/(a+b)), n (%) [95%CI] / 64/71 (90.1%) [83.2-97.0] / 55/61 (90.2%) [82.7-97.7] / 50/54 (92.6%) [85.6-99.6] / 14/16 (87.5%) [71.3-100.0] / 15/16 (93.8%) [81.9-100.0] / 13/15 (86.7%) [69.5-100.0]
Specificity (d/(c+d)), n (%) [95%CI] / 164/462 (35.5%) [31.1-39.9] / 122/342 (35.7%) [30.6-40.8] / 100/301 (33.2%) [27.9-38.5] / 15/108 (13.9%) [7.3-19.3] / 10/90 (13.9%) [7.4-20.3] / 10/87 (11.5%) [4.9-18.2]
Positive predictive valued, % / 17.2% / 20.0% / 19.8% / 13.4% / 16.2% / 14.8%
Negative predictive valued, % / 95.9% / 95.3% / 96.2% / 88.0% / 92.6% / 82.9%
Likelihood ratio ([a/(a+b)]/[c/(c+d]) / 1.4 / 1.4 / 1.4 / 1.1 / 1.1 / 1.0

a Total vitamin B12 serum level < 395 pg/ml; serum holoTC level < 67 pmol/l.

b Only subjects with normal renal function as defined as ≤ 106µg/l (males), ≤ 80 µmol/l (female) were included into the analyses.

c Subcohort of subjects with peripheral neuropathy and/or subacute combined degeneration.

d Calculated using the Bayes' theorem.