Here we focus on discrimination problems where the number of predictors substantially exceeds the sample size and we propose a Bayesian variable selection approach to multinomial probit models. Our method makes use of mixture priors and Markov chain Monte Carlo techniques to select sets of variables that differ among the classes. We apply our methodology to a problem in functional genomics using gene expression profiling data. The aim of the analysis is to identify molecular signatures that characterize two different stages of rheumatoid arthritis.

ObjectiveTo investigate whether antidrug antibodies and/or drug non‐trough levels predict the long‐term treatment response in a large cohort of patients with rheumatoid arthritis (RA) treated with adalimumab or etanercept and to identify factors influencing antidrug antibody and drug levels to optimize future treatment decisions.MethodsA total of 331 patients from an observational prospective cohort were selected (160 patients treated with adalimumab and 171 treated with etanercept). Antidrug antibody levels were measured by radioimmunoassay, and drug levels were measured by enzyme‐linked immunosorbent assay in 835 serial serum samples obtained 3, 6, and 12 months after initiation of therapy. The association between antidrug antibodies and drug non‐trough levels and the treatment response (change in the Disease Activity Score in 28 joints) was evaluated.ResultsAmong patients who completed 12 months of followup, antidrug antibodies were detected in 24.8% of those receiving adalimumab (31 of 125) and in none of those receiving etanercept. At 3 months, antidrug antibody formation and low adalimumab levels were significant predictors of no response according to the European League Against Rheumatism (EULAR) criteria at 12 months (area under the receiver operating characteristic curve 0.71 [95% confidence interval (95% CI) 0.57, 0.85]). Antidrug antibody–positive patients received lower median dosages of methotrexate compared with antidrug antibody–negative patients (15 mg/week versus 20 mg/week; P = 0.01) and had a longer disease duration (14.0 versus 7.7 years; P = 0.03). The adalimumab level was the best predictor of change in the DAS28 at 12 months, after adjustment for confounders (regression coefficient 0.060 [95% CI 0.015, 0.10], P = 0.009). Etanercept levels were associated with the EULAR response at 12 months (regression coefficient 0.088 [95% CI 0.019, 0.16], P = 0.012); however, this difference was not significant after adjustment. A body mass index of ≥30 kg/m2 and poor adherence were associated with lower drug levels.ConclusionPharmacologic testing in anti–tumor necrosis factor–treated patients is clinically useful even in the absence of trough levels. At 3 months, antidrug antibodies and low adalimumab levels are significant predictors of no response according to the EULAR criteria at 12 months.

During thrombopoiesis, maturing megakaryocytes (MKs) migrate within the complex bone marrow stromal microenvironment from the proliferative osteoblastic niche to the capillary-rich vascular niche where proplatelet formation and platelet release occurs. This physiologic process involves proliferation, differentiation, migration, and maturation of MKs before platelet production occurs. In this study, we report a role for the glycoprotein PECAM-1 in thrombopoiesis. We show that following induced thrombocytopenia, recovery of the peripheral platelet count is impaired in PECAM-1-deficient mice. Whereas MK maturation, proplatelet formation, and platelet production under in vitro conditions were unaffected, we identified a migration defect in PECAM-1-deficient MKs in response to a gradient of stromal cell-derived factor 1 (SDF1), a major chemokine regulating MK migration within the bone marrow. This defect could be explained by defective PECAM-1 ؊/؊ MK polarization of the SDF1 receptor CXCR4 and an increase in adhesion to immobilized bone marrow matrix proteins that can be ex- IntroductionMegakaryocytopoiesis involves proliferation and differentiation of megakaryocyte (MK) progenitors to a large, terminally differentiated cell with a multi-lobulated, polyploid nucleus. Nuclear maturation, a process known as endoreplication, proceeds in concert with cytoplasmic maturation and expression of platelet surface markers including the glycoprotein receptors IIb/IIIa, GPIb, GPIX, and GPVI. As the MK matures and differentiates, it migrates to sinusoidal bone marrow endothelial cells where it forms transendothelial projections called proplatelets that release 1000 to 5000 platelets per MK into the intravascular space. [1][2][3][4][5] Thrombopoietin (TPO) participates in the humoral regulation of thrombopoiesis. TPO is produced constitutively in the liver and by bone marrow stromal cells and its levels are regulated by binding to the receptor c-Mpl expressed on platelets. 6 This has the net effect of reducing the concentration of TPO in the circulation and thereby inhibiting differentiation of progenitor cells along the MK lineage. Thus, megakaryocytopoiesis and platelet count are directly regulated by circulating TPO. 2 A key step in thrombopoiesis is migration of maturing MKs from the proliferative osteoblastic niche within the bone marrow microenvironment, where hematopoietic stem cells reside, to the capillary-rich vascular niche, where proplatelets are formed. 6 This process is regulated by a variety of chemokines and cytokines, as well as by adhesive interactions with interstitial cells and extracellular matrix proteins. For example, the chemokine SDF1 directs movement of MK progenitors through its receptor CXCR4 from the proliferative "osteoblastic niche" to the "vascular niche," where platelets are formed. 6 SDF1 therefore acts in combination with TPO to promote differentiation of MK progenitor cells to mature MKs. 7,8 In addition, SDF1 promotes the interaction and transmigration of mature MKs through bone marrow endothel...