Characteristics of the cohort.

a<p>IFNβ preparation could be assigned to 358 of the 364 NAb positive patients, while the type of preparation used was unspecified for 6 NAb positive patients.</p><p>Abbreviations: IQR = interquartile range, i.m. = intramuscular, s.c. = subcutaneous, TRU/ml = tenfold reduction units per milliliter, IFNβ = interferon beta, NAb = neutralizing antibodies</p

HLA association to development of NAbs and biologically relevant titers.

a<p>Major HLA alleles (>5% allele frequency) nominally associated or previously reported to be associated with development of NAbs and biologically relevant titers are presented. All HLA alleles can be found in <b><a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0090479#pone.0090479.s002" target="_blank">Table S2</a></b> and <b>S3</b>.</p>b<p>nominal <i>P</i>-values assessed by Chi square test,</p>c<p>Bonferroni corrected <i>P</i>-values (76 allele groups tested).</p><p>Abbreviations: BRT = biologically relevant titers, C.I. = confidence interval, NAb = neutralizing antibodies, OR = odds ratio.</p

Carrier frequency and absolute risk for HLA allele groups associated to NAb development and biologically relevant titers^a.

a<p>All HLA allele groups can be found in <b><a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0090479#pone.0090479.s005" target="_blank">Table S5</a></b>.</p>b<p>Treatment only is the frequency of NAb development and biologically relevant titers for each treatment regardless of genotype.</p>c<p>The absolute risk for each HLA allele group is calculated with Bayes' theorem and assessed based on frequency and impact on NAb development.</p>d<p>Nominal <i>P</i>-values from Fishers exact test.</p>e<p>Bonferroni corrected <i>P</i>-values (allele groups tested: 12 tests for i.m. IFNβ-1a, 19 tests for IFNβ-1b, 38 for s.c. IFNβ-1a).</p><p>Abbreviations: AR = absolute risk, C.I. = confidence interval, OR = odds ratio, IFNβ = interferon beta, n/a = not applicable, NAb = neutralizing antibodies.</p

Independence of the protective class I haplotype from <i>DRB1</i><i>*</i><i>15</i> demonstrated in two ways.

<p>Counts are made in number of chromosomes carrying the haplotypes estimated in UNPHASED within the cohort. “Haplotype +” was all chromosomes with both <i>A*02</i>, <i>C*05</i> and <i>B*12</i> disregarding the <i>DRB1</i> locus, “Haplotype –”were all chromosomes that did not have all three allele groups (<i>A*02</i>, <i>C*05</i> and <i>B*12</i>) at once, still disregarding DRB1. “<i>DRB1*15</i>+” was all chromosomes carrying <i>DRB1*15</i> disregarding class I allele groups and vice versa for the “<i>DRB1*15</i> –”.</p>*<p>) Odds ratio for the class I haplotype within <i>DRB1*15</i> positive and negative haplotypes respectively.</p>**<p>) Odds ratio for <i>DRB1*15</i> within the class I haplotype and class I haplotype negative respectively. Note: Class I haplotype negative chromosomes can carry parts of the protective haplotype (i.e. <i>A*02</i> but in that case not <i>C*05</i> and/or <i>B*12</i>).</p

Risk carried by each of the nominally significant allele groups in the logistic regression model for carriage coded <i>DRB1*15</i> negative and positive strata.

<p>Country of origin and gender were included in the models as covariates. <i>DRB1*15</i> was coded as dose (0,1,2), all other allele groups were coded for carriage (0,1).</p

Interaction analysis showing evidence of interaction between <i>DRB1</i><i>*</i><i>15</i> and other allele groups influencing the risk of MS.

*<p> = risk is coded as absence of this allele group since it is nominally protective.</p>#<p> = Model has significantly better fit than one with only the two variables by themselves (no interaction term).</p

Odds ratios for haplotypes carrying any combination of <i>A*02</i>, <i>C*05</i> and <i>B*12</i>.

<p>Odds ratios for haplotypes containing one or two of the allele groups of the protective class I haplotype compared to the full protective class I haplotype disregarding the <i>DRB1</i> locus. Chromosomes carrying both <i>A*02</i> and <i>B*12</i> was the only combination within this setting that had the same risk as the protective haplotype, the risk of MS was significantly higher for all other combinations.“+” = Chromosomes carrying the allele group specified to the left, “H−” = chromosomes carrying other allele group than the one specified to the left (i.e. not the complete protective haplotype). OR = odds ratio with 95% confidence interval, nominal p-value and Bonferroni corrected p-values derived from chi square test with full protective haplotype as reference.</p

Odds ratios for chromosomes carrying only the protective haplotype or <i>DRB1*15</i> or both.

<p>Chromosomes carrying both <i>DRB1*15</i> and the protective class I haplotype do not differ in risk of MS from chromosomes not carrying either of them (reference). <i>DRB1*15</i> carriage increase risk of MS significantly and carriage of the class I haplotype significantly decrease risk of MS. Counts are measured in chromosomes and only individuals with estimated haplotypes with a probability of more than 80% were included. “+” = Chromosomes positive for the protective haplotype or <i>DRB1*15</i>, “−” and “H−” = chromosomes negative for <i>DRB1*15</i> or the protective haplotype. OR = odds ratio with 95% confidence interval, nominal p-value and Bonferroni corrected p-values derived from chi square test with doubly negative chromosomes as reference.</p

Major allele groups and their frequencies in the Scandinavian sample set.

<p>Some individuals were not genotyped deeply enough to distinguish allele groups. Therefore, major allele groups containing several allele groups were created when needed.</p>†<p>Figure in parenthesis is the percentage of this allele group in this major allele group.</p

Risks carried by each of the nominally significant allele groups from the final logistic regression analyses.

<p>FDR = False discovery rate, performed in R, based on the paper <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0036779#pone.0036779-Rothman1" target="_blank">[37]</a>.</p