For the analysis, an inhibitor was defined as a current or history of an inhibitor ≥1 Bethesda unit (BU). The procedures followed were in accordance C59 wnt cost with the ethical standards of the responsible committees on human experimentation for all three cohorts and with the Helsinki Declaration. The MIBS and HIGS

are registered at ClinicalTrials.gov. To determine factor VIII haplotypes, four non-synonymous SNPs on the F8 gene, G1679A, A2554G, C3951G and A6940G, were genotyped using the Assay-on-Demand from Applied Biosystems standard protocols (www.AppliedBiosystems.com). Haplotypes were constructed using the four markers that were genotyped. Because the population was almost exclusively male (99.9%), all but one individual was hemizygous, as all markers are located on the X chromosome. Typing was completed for all but 7.1% of the markers. An EM algorithm [11, 12] was used to infer haplotypes for individuals with missing information. Individuals with missing Vincristine genotypes were assigned the haplotype that demonstrated the highest posterior probability. One of the 833 study participants was not haplotyped, reducing the analysis sample to 832. Approximately 96% of the participants in the HIGS Combined Cohort were F8 mutation typed. The remaining 4% of subjects were not typed for either technical reasons or lack of sufficient DNA. For HIGS and MIBS, if the F8 gene mutation was

not already documented at enrolment, a blood sample was sent for determination to the Institute of Experimental Haematology and Transfusion Medicine, Bonn, Germany. Standard methods for the analyses of the F8 gene were used [13]. In HGDS, the presence or absence of an inversion mutation in the F8 gene was determined for 58% of the HGDS cohort [14]. The remaining HGDS samples were mutation typed at the

Institute of Experimental Haematology and Transfusion Medicine, Bonn, Germany by the methods outlined above. Class II HLA genotyping was performed using high-resolution (4-digit) sequence based typing (SBT) protocols recommended by the 13th International Histocompatibility Workshop [15]. Typing was completed for 99.9% of the Combined Cohort. The recombinant FVIII replacement products included MCE公司 in the current analysis were as follow: Recombinate, antihaemophilic factor concentrate manufactured by Baxter Healthcare Corporation (Westlake Village, CA, USA) [16, 17], derived from H2 proteins; Advate, antihaemophilic factor produced by a plasma- and albumin-free method, manufactured by Baxter Healthcare Corporation [18], also derived from H2 proteins; and Kogenate, antihaemophilic factor manufactured by Bayer HealthCare Pharmaceuticals (Berkeley, CA, USA) [19], derived from H1 proteins. Association tests, including Fisher’s exact test, were carried out using two by two tables to evaluate the probability of inhibitor occurrence. Generalized estimating equations (GEE) models were used to account for the relatedness of participants.