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Table 2 Analysis of number of case reports showing improvement or impairment, associated with ERT in a specific outcome, based on a weak confirmatory method

From: Agreement between results of meta-analyses from case reports and clinical studies, regarding efficacy and safety of idursulfase therapy in patients with mucopolysaccharidosis type II (MPS-II). A new tool for evidence-based medicine in rare diseases

RANK Outcomes & (SOE score*) Nr. [+] / Total cases p-value** FDR 10% Critical value*** Evidence group****
1 uGAGs (Moderate) 20/44 < 0.0001 < 0.009 Acceptable
2 6MWT (Low) 15/44 < 0.0001 < 0.027 Acceptable
3 Liver V (Moderate) 13/44 < 0.0001 < 0.027 Acceptable
4 QoL (Insufficient) 8/44 0.014 < 0.036 Acceptable
5 Antibodies (Moderate) 6/44 0.022 < 0.045 Acceptable
6 Growth height (Low) 5/44 0.067 N.S (> 0.055) Unacceptable
6 JROM (Insufficient) 5/44 0.067 N.S (> 0.055) Unacceptable
7 Pulmonary function (Low) 4/44 0.177 N.S (> 0.072) Unacceptable
8 IRR (Low) 2/44 0.653 N.S (> 0.064) Unacceptable
9 Sleep apnea (Insufficient) 1/44 0.895 N.S (> 0.082) Unacceptable
10 Cardiac (Insufficient) 0/44 1 N.S (> 0.091) Unacceptable
  1. Legend:The improvement is defined in accordance with the weak confirmatory method. The impairment was declared when IRR caused a change in ERT dose.
  2. 6MWT 6-min walk test, FDR False discovery rate (Benjamini-Hochberg procedure), IRR infusion-related reaction, JROM joint range of motion, Nr. [+] Number of case reports showing improvement or impairment in IRR associated with ERT in a specific outcome, QoL Quality of life, SOE Strength of evidence, uGAGs Urinary glycosaminoglycans.
  3. *The SOE classification has been previously published in Bradley et al. [12]
  4. ** The analysis assessed whether the percentage of case reports showing a modification in a specific outcome was statistically higher than 5% (null hypothesis, H0). The p-value was performed with a one-sided binomial test
  5. *** FDR critical value: Outcomes with p-values lower than FDR critical value are considered as modified by ERT (Multiplicity adjustment). The FDR critical value is calculated by ranking the outcomes analyzed from lowest to highest p-value. The rank (r) is divided by number of outcomes and multiplied by the accepted 10% rate of false discoveries. The lowest rank of tied p-values was used because the critical value is computed is lower, and is more conservative for a specific outcome as modified by ERT. However, the same outcomes were classified as modified by ERT when the highest or mean rank was used for ties
  6. **** The outcomes showing a p-value lower than the FDR 10% critical value were classified in acceptable evidence groups (shadow rows). The outcomes showed a p-value higher than the FDR 10% critical value and were classified in unacceptable evidence groups (white rows). In bold: Moderate to high SOE categories