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- Knevel, R., et al.
(author)
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Genetic variants in IL15 associate with progression of joint destruction in rheumatoid arthritis: a multicohort study
- 2012
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In: Annals of the Rheumatic Diseases. - : BMJ. - 1468-2060 .- 0003-4967. ; 71:10, s. 1651-1657
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Journal article (peer-reviewed)abstract
- Background Interleukin (IL)-15 levels are increased in serum, synovium and bone marrow of patients with rheumatoid arthritis (RA). IL-15 influences both the innate and the adaptive immune response; its major role is activation and proliferation of T cells. There are also emerging data that IL-15 affects osteoclastogenesis. The authors investigated the association of genetic variants in IL15 with the rate of joint destruction in RA. Method 1418 patients with 4885 x-ray sets of both hands and feet of four independent data sets were studied. First, explorative analyses were performed on 600 patients with early RA enrolled in the Leiden Early Arthritis Clinic. Twenty-five single-nucleotide polymorphisms (SNPs) tagging IL-15 were tested. Second, SNPs with significant associations in the explorative phase were genotyped in data sets from Groningen, Sheffield and Lund. In each data set, the relative increase of the progression rate per year in the presence of a genotype was assessed. Subsequently, data were summarised in an inverse weighting meta-analysis. Results Five SNPs were significantly associated with rate of joint destruction in phase 1 and typed in the other data sets. Patients homozygous for rs7667746, rs7665842, rs2322182, rs6821171 and rs4371699 had respectively 0.94-, 1.04-, 1.09-, 1.09- and 1.09- fold rate of joint destruction compared to other patients (p = 4.0x10(-6), p = 3.8x10(-4), p = 5.0x10(-3), p = 5.0x10(-3) and p = 9.4x10(-3)). Discussion Independent replication was not obtained, possibly due to insufficient power. Meta-analyses of all data sets combined resulted in significant results for four SNPs (rs7667746, p < 0.001; rs7665842, p < 0.001; rs4371699, p = 0.01; rs6821171, p = 0.01). These SNPs were also significant after correction for multiple testing. Conclusion Genetic variants in IL-15 are associated with progression of joint destruction in RA.
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- Knevel, R., et al.
(author)
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A genetic variant in granzyme B is associated with progression of joint destruction in rheumatoid arthritis
- 2013
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In: Arthritis and Rheumatism. - : Wiley. - 1529-0131 .- 0004-3591. ; 65:3, s. 582-589
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Journal article (peer-reviewed)abstract
- Objective Genetic factors account for an estimated 4558% of the variance in joint destruction in rheumatoid arthritis (RA). The serine proteinase granzyme B induces target cell apoptosis, and several in vitro studies suggest that granzyme B is involved in apoptosis of chondrocytes. Serum levels of granzyme B are increased in RA and are also associated with radiographic erosions. The aim of this study was to investigate GZMB as a candidate gene accounting for the severity of joint destruction in RA. Methods A total of 1,418 patients with 4,885 radiograph sets of the hands and feet from 4 independent cohorts were studied. First, explorative analyses were performed in 600 RA patients in the Leiden Early Arthritis Clinic cohort. Fifteen single-nucleotide polymorphisms (SNPs) tagging GZMB were tested. Significantly associated SNPs were genotyped in data sets representing patients from the Groningen, Sheffield, and Lund cohorts. In each data set, the relative increase in the annual rate of progression in the presence of a genotype was assessed. Data were summarized in a meta-analysis. The association of GZMB with the RNA expression level of the GZMB genomic region was tested by mapping expression quantitative trait loci (QTLs) on 1,469 whole blood samples. Results SNP rs8192916 was significantly associated with the rate of joint destruction in the first cohort and in the meta-analysis of all data sets. Patients homozygous for the minor allele of rs8192916 had a higher rate of joint destruction per year compared with other patients (P = 7.8 x 104). Expression QTL of GZMB identified higher expression in the presence of the minor allele of rs8192916 (P = 2.27 x 105). Conclusion SNP rs8192916 located in GZMB is associated with the progression of joint destruction in RA as well as with RNA expression in whole blood.
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- Van Hamersveld, K. T., et al.
(author)
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Fixation and clinical outcome of uncemented peri-apatite-coated versus cemented total knee arthroplasty : Five-year follow-up of a randomised controlled trial , using radiostereometric analysis (RSA)
- 2017
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In: The Bone & Joint Journal. - 2049-4394. ; 99B:11, s. 1467-1476
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Research review (peer-reviewed)abstract
- Aims The optimal method of tibial component fixation remains uncertain in total knee arthroplasty (TKA). Hydroxyapatite coatings have been applied to improve bone ingrowth in uncemented designs, but may only coat the directly accessible surface. As peri-apatite (PA) is solution deposited, this may increase the coverage of the implant surface and thereby fixation. We assessed the tibial component fixation of uncemented PA-coated TKAs versus cemented TKAs. Patients and Methods Patients were randomised to PA-coated or cemented TKAs. In 60 patients (30 in each group), radiostereometric analysis of tibial component migration was evaluated as the primary outcome at baseline, three months post-operatively and at one, two and five years. A linear mixed-effects model was used to analyse the repeated measurements. Results After five years of follow-up, one (cemented) component was revised due to ligament instability. Overall, uncemented PA-coated tibial components migrated significantly more (p = 0.003), with the mean maximum total point motion (MTPM) at five years being 0.62 mm (95% confidence intervals (CI) 0.49 to 0.76) for cemented tibial components and 0.97 mm (95% CI 0.81 to 1.15) for PA-coated tibial components in TKA. However, between three months and five years the cemented TKAs migrated significantly more (p = 0.02), displaying a MTPM of 0.27 mm (95% CI, 0.19 to 0.36) versus 0.13 mm (95% CI, 0.01 to 0.25) for PAcoated tibial components. One implant in each group was considered at risk for aseptic loosening due to continuous migration after five years of follow-up, albeit with different migration patterns for each group (i.e. higher initial migration but diminishing over time for the PA-coated component versus gradually increasing migration for the cemented component). Conclusion The tibial components of PA-coated TKAs showed more overall migration compared with the tibial components of cemented TKAs. However, post hoc analysis showed that this difference was caused by higher migration of PA-coated components in the first three months, after which a stable migration pattern was observed. Clinically, there was no significant difference in outcome between the groups.
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- Signorelli, M., et al.
(author)
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Penalized regression calibration : A method for the prediction of survival outcomes using complex longitudinal and high-dimensional data
- 2021
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In: Statistics in Medicine. - : Wiley. - 0277-6715 .- 1097-0258. ; 40:27, s. 6178-6196
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Journal article (peer-reviewed)abstract
- Longitudinal and high-dimensional measurements have become increasingly common in biomedical research. However, methods to predict survival outcomes using covariates that are both longitudinal and high-dimensional are currently missing. In this article, we propose penalized regression calibration (PRC), a method that can be employed to predict survival in such situations. PRC comprises three modeling steps: First, the trajectories described by the longitudinal predictors are flexibly modeled through the specification of multivariate mixed effects models. Second, subject-specific summaries of the longitudinal trajectories are derived from the fitted mixed models. Third, the time to event outcome is predicted using the subject-specific summaries as covariates in a penalized Cox model. To ensure a proper internal validation of the fitted PRC models, we furthermore develop a cluster bootstrap optimism correction procedure that allows to correct for the optimistic bias of apparent measures of predictiveness. PRC and the CBOCP are implemented in the R package pencal, available from CRAN. After studying the behavior of PRC via simulations, we conclude by illustrating an application of PRC to data from an observational study that involved patients affected by Duchenne muscular dystrophy, where the goal is predict time to loss of ambulation using longitudinal blood biomarkers.
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