Elevated white blood cell levels and thrombotic events in patients with polycythemia vera: a real-world analysis of veterans health administration data

Background: Patients with polycythemia vera (PV) have a substantial risk of thrombotic events (TEs). The objective of the present analysis was to describe the association between white blood cell (WBC) levels and occurrence of TEs among patients with PV from a large real-world population. Patients and Methods: The present retrospective analysis using Veterans Health Administration claims data (October 1, 2005, to September 30, 2012) evaluated adult patients assigned to 4 WBC count categories (WBC count < 7.0, 7.0-8.4, 8.5 to < 11.0, and ≥ 11.0 × 109/L) to compare the risk of TEs (reference, WBC count, < 7.0 × 109/L group). Analysis was performed using a Cox proportional hazards model, considering WBC status as a time-dependent covariate. Results: Of the 1565 patients with PV included in the present analysis, the WBC count was < 7.0 × 109/L for 428 (27.3%), 7.0 to 8.4 × 109/L for 375 (24.0%), 8.5 to < 11.0 × 109/L for 284 (18.1%), and ≥ 11.0 × 109/L for 478 (30.5%). Of the 1565 patients, 390 (24.9%) had experienced a TE during the study period. The mean follow-up ranged from 3.6 to 4.5 years. Compared with the reference group (WBC count < 7.0 ×109/L), the hazard ratio for TEs was 1.10 (95% confidence interval [CI], 0.82-1.48; P = .5395), 1.47 (95% CI, 1.10-1.96; P = .0097), and 1.87 (95% CI, 1.44-2.43; P < .0001) for patients with a WBC count of 7.0 to 8.4, 8.5 to < 11.0, and ≥ 11.0 ×109/L, respectively. Conclusion: A positive, significant association between an increased WBC count of ≥ 8.5 ×109/L and the occurrence of TEs was observed in patients with PV. The potential thrombogenic role of WBCs in patients with PV supports the continued inclusion of WBC count control in disease management and evaluation of the response to therapy. © 2019 The AuthorsPatients with polycythemia vera (PV) have a substantial risk of thrombotic events (TEs). In the present retrospective analysis using Veterans Health Administration claims data, 25% of 1565 patients experienced a TE during follow-up. We observed a positive, significant association between white blood cell (WBC) counts ≥ 8.5 × 109/L and TE occurrence (reference, WBC count < 7.0 × 109/L), supporting continued inclusion of WBC count control in disease management. © 2019 The AuthorsIncyte Corporation (Wilmington, DE)WOS:000513918800013Scopus - Affiliation ID: 60105072PMID: 31865003Science Citation Index ExpandedQ3ArticleUluslararası işbirliği ile yapılan - EVETŞubat2020YÖK - 2019-2

Correlation and variance stabilization in the two group comparison case in high dimensional data under dependencies

Doctor of PhilosophyDepartment of StatisticsGary L. GadburyMultiple testing research has undergone renewed focus in recent years as advances in high throughput technologies have produced data on unprecedented scales. Much of the focus has been on false discovery rates (FDR) and related quantities that are estimated (or controlled for) in large scale multiple testing situations. Recent papers by Efron have directly addressed this issue and incorporated measures to account for high-dimensional correlation structure when estimating false discovery rates and when estimating a density. Other authors also have proposed methods to control or estimate FDR under dependencies with certain assumptions. However, not much focus is given to the stability of the results obtained under dependencies in the literature. This work begins by demonstrating the effect of dependence structure on the variance of the number of discoveries and the false discovery proportion (FDP). A variance of the number of discoveries is shown and the density of a test statistic, conditioned on the status (reject or failure to reject) of a different correlated test, is derived. A closed form solution to the correlation between test statistics is also derived. This correlation is a combination of correlations and variances of the data within groups being compared. It is shown that these correlations among the test statistics affect the conditional density and alters the threshold for significance of a correlated test, causing instability in the results. The concept of performing tests within networks, Conditional Network Testing (CNT) is introduced. This method is based on the conditional density mentioned above and uses the correlation between test statistics to construct networks. A method to simulate realistic data with preserved dependence structures is also presented. CNT is evaluated using simple simulations and the proposed simulation method. In addition, existing methods that controls false discovery rates are used on t-tests and CNT for comparing performance. It was shown that the false discovery proportion and type I error proportions are smaller when using CNT versus using t-tests and, in general, results are more stable when applied to CNT. Finally, applications and steps to further improve CNT are discussed

markers of iron deficiency in patients with polycythemia vera receiving ruxolitinib or best available therapy

Abstract Polycythemia vera (PV) is characterized by erythropoiesis and JAK2- activating mutations, with increased risks of morbidity and mortality. Most patients with PV are iron deficient, and treatment often includes hematocrit control with phlebotomy, which may exacerbate iron deficiency-associated complications. The phase 3 RESPONSE trial evaluated the JAK1/JAK2 inhibitor ruxolitinib (n = 110) versus best available therapy (BAT; n = 112) in patients with PV who were hydroxyurea-resistant/intolerant. Ruxolitinib was superior to BAT for hematocrit control, reduction in splenomegaly, and blood count normalization. This exploratory analysis, the first to evaluate iron status in a prospective study of patients with PV, investigated ruxolitinib effects on 7 serum iron markers and iron deficiency-related patient-reported outcomes (PRO). Among patients with evidence of baseline iron deficiency, ruxolitinib was associated with normalization of iron marker levels, compared with lesser improvement with BAT. Iron levels remained stable in ruxolitinib patients with normal iron levels at baseline. Regardless of baseline iron status, treatment with ruxolitinib was associated with improvements in concentration problems, cognitive function, dizziness, fatigue, headaches, and inactivity, although improvements were generally greater among patients with baseline iron deficiency. The improvements in iron deficiency markers and PROs observed with ruxolitinib are suggestive of clinical benefits that warrant further exploration