Improved curve fits to summary survival data: application to economic evaluation of health technologies

addresses: Peninsula College of Medicine and Dentistry, Veysey Building, Salmon Pool Lane, Exeter, EX2 4SG, UK. [email protected]: PMCID: PMC3198983types: Journal Article; Research Support, Non-U.S. Gov't© 2011 Hoyle and Henley; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Mean costs and quality-adjusted-life-years are central to the cost-effectiveness of health technologies. They are often calculated from time to event curves such as for overall survival and progression-free survival. Ideally, estimates should be obtained from fitting an appropriate parametric model to individual patient data. However, such data are usually not available to independent researchers. Instead, it is common to fit curves to summary Kaplan-Meier graphs, either by regression or by least squares. Here, a more accurate method of fitting survival curves to summary survival data is described

Epithelial-Associated Inflammatory Pathways Underlie Residual Asthma Exacerbations in Urban Children Treated with Mepolizumab Therapy

Rationale: Identification of airway inflammatory pathways in asthma has proven essential to understanding mechanisms of disease and has led to effective personalized treatment with biologic therapies. However, relatively little is known about patterns of airway inflammation at the time of respiratory illnesses and how such patterns relate to responsiveness to biologic therapies. Methods: The MUPPITS-1 (n=106) and MUPPITS-2 (n=290) studies investigated asthma exacerbations in urban children with exacerbation-prone asthma and ≥150/microliter blood eosinophils. Children in both studies received guidelines-based asthma care; in MUPPITS-2, participants were additionally randomized (1:1) to placebo or mepolizumab. Nasal lavage samples were collected during respiratory illnesses for RNA-sequencing and analyzed by modular analysis to assess genome-wide expression patterns associated with exacerbation illnesses. Results: Among 284 illnesses, exacerbations that occurred in the absence of mepolizumab therapy showed significantly higher upregulation of eosinophil associated inflammatory pathways (fold change values [FC]=1.27-1.43, p-values\u3c0.05), including a Type-2 inflammation module composed of eosinophil, mast cell, and IL-13 response genes. In contrast, exacerbations that occurred while on mepolizumab therapy showed significantly higher upregulation of several epithelial inflammatory pathways (FC=1.36-1.64, p-values\u3c0.05) including TGF-β/Smad3 signaling, extracellular matrix production, and epidermal growth factor receptor signaling. Conclusions: These results indicate that novel inflammatory pathways, likely originating from the airway epithelium and distinct from Type-2 or eosinophilic inflammation, drive residual exacerbations that occur in children treated with mepolizumab therapy added to guideline-based care. These findings identify likely mechanisms of persistent disease expression in these children despite significant depletion of eosinophils and can identify novel treatment targets for future studies

The Effect of Subcutaneous German Cockroach Immunotherapy (SCIT) on Nasal Allergen Challenge (NAC) and Cockroach-specific Antibody Responses Among Urban Children and Adolescents

Rationale: Cockroach allergy contributes to asthma and rhinitis morbidity among many urban children. Treatment with cockroach SCIT could be beneficial. Methods: 8-17 year-old children with mild-moderate asthma from 11 urban sites participated in a randomized double-blind placebo-controlled SCIT trial using non-standardized, glycerinated German cockroach extract. Positive cockroach skin tests, cockroach-specific IgE, and nasal challenge response with total nasal symptom scores (TNSS) ≥6 or maximal sneeze scores of 3 during a graded NAC were required for enrollment. Following dose escalation, 0.4 ml of undiluted extract was targeted for maintenance dosing (∼7 mcg Bla g2/dose). The primary endpoint was change in NAC-induced mean TNSS from baseline to one year post randomization. Changes in cockroach-specific IgE (CRsIgE) and IgG4 (CRsIgG4) were also analyzed. Results: Mean TNSS did not significantly change from baseline in either group (placebo n=29, SCIT n=28). There was no significant difference in the change in mean TNSS between placebo and SCIT [−0.79±0.35 vs. −1.02±0.37, respectively, difference=0.2(−1.15, 0.70), p=0.63]. Baseline CRsIgE and CRsIgG4 didn’t differ between groups. Mean CRsIgE decreased in both groups following treatment: 3.6 to 2.3 kU/L (0.64 fold change), p=0.015 and 8.3 to 4.2 kU/L (0.51 fold change), p\u3c0.001 in placebo and SCIT respectively, but did not differ between groups [p=0.33]. Significant increases in CRsIgG4 post-treatment were observed among SCIT recipients only: 0.07 to 12.3 mg/L (176 fold change), p\u3c0.001. Conclusions: Cockroach SCIT increased CRsIgG4 levels but did not significantly alter NAC-induced TNSS responses. The extent to which NAC in these children may reflect clinical efficacy for rhinitis or asthma is uncertain

Text mining for biology - the way forward: opinions from leading scientists

This article collects opinions from leading scientists about how text mining can provide better access to the biological literature, how the scientific community can help with this process, what the next steps are, and what role future BioCreative evaluations can play. The responses identify several broad themes, including the possibility of fusing literature and biological databases through text mining; the need for user interfaces tailored to different classes of users and supporting community-based annotation; the importance of scaling text mining technology and inserting it into larger workflows; and suggestions for additional challenge evaluations, new applications, and additional resources needed to make progress

Cytoplasmic p53 couples oncogene-driven glucose metabolism to apoptosis and is a therapeutic target in glioblastoma.

Cross-talk among oncogenic signaling and metabolic pathways may create opportunities for new therapeutic strategies in cancer. Here we show that although acute inhibition of EGFR-driven glucose metabolism induces only minimal cell death, it lowers the apoptotic threshold in a subset of patient-derived glioblastoma (GBM) cells. Mechanistic studies revealed that after attenuated glucose consumption, Bcl-xL blocks cytoplasmic p53 from triggering intrinsic apoptosis. Consequently, targeting of EGFR-driven glucose metabolism in combination with pharmacological stabilization of p53 with the brain-penetrant small molecule idasanutlin resulted in synthetic lethality in orthotopic glioblastoma xenograft models. Notably, neither the degree of EGFR-signaling inhibition nor genetic analysis of EGFR was sufficient to predict sensitivity to this therapeutic combination. However, detection of rapid inhibitory effects on [18F]fluorodeoxyglucose uptake, assessed through noninvasive positron emission tomography, was an effective predictive biomarker of response in vivo. Together, these studies identify a crucial link among oncogene signaling, glucose metabolism, and cytoplasmic p53, which may potentially be exploited for combination therapy in GBM and possibly other malignancies

Mepolizumab Alters Regulation of Airway Type-2 Inflammation in Urban Children with Asthma by Disrupting Eosinophil Gene Expression but Enhancing Mast Cell and Epithelial Pathways

Rationale: Mepolizumab (anti-IL5) reduces asthma exacerbations in urban children. We previously utilized nasal transcriptomics to identify inflammatory pathways (gene co-expression modules) associated with exacerbations despite this therapy. To understand mepolizumab’s precise impact on these pathways, we assess gene co-expression and loss of correlation, “decoherence,” using differential co-expression network analyses. Methods: 290 urban children (6-17 years) with exacerbation-prone asthma and blood eosinophils ≥150/microliter were randomized (1:1) to q4 week placebo or mepolizumab injections added to guideline-based care for 52 weeks. Nasal lavage samples were collected before and during treatment for RNA-sequencing. Differential co-expression of gene networks was evaluated to assess interactions and regulatory aspects of type-2 and eosinophilic airway inflammation. Results: Mepolizumab, but not placebo, significantly reduced the overall expression of an established type-2 inflammation gene co-expression module (fold change=0.77, p=0.002) enriched for eosinophil, mast cell, and epithelial IL-13 response genes (242 genes). Mepolizumab uncoupled co-expression of genes in this pathway. During mepolizumab, but not placebo treatment, there was significant loss of correlation among eosinophil-specific genes including RNASE2 (EDN), RNASE3 (ECP), CLC, SIGLEC8, and IL5RA contrasting a reciprocal increase in correlation among mast cell-specific genes (TPSAB1, CPA3, FCER1A), T2 cytokines (IL4, IL5, and IL13), and POSTN. Conclusions: These results suggest mepolizumab disrupts the regulatory interactions of gene co-expression among airway eosinophils, mast cells and epithelium by interrupting transcription regulation in eosinophils with enhancement in mast cell and epithelial inflammation. This paradoxical effect may contribute to an incomplete reduction of asthma exacerbations and demonstrates how differential co-expression network analyses can identify targets for more precise therapies

Measurement of fractionated plasma metanephrines for exclusion of pheochromocytoma: Can specificity be improved by adjustment for age?

BACKGROUND: Biochemical testing for pheochromocytoma by measurement of fractionated plasma metanephrines is limited by false positive rates of up to 18% in people without known genetic predisposition to the disease. The plasma normetanephrine fraction is responsible for most false positives and plasma normetanephrine increases with age. The objective of this study was to determine if we could improve the specificity of fractionated plasma measurements, by statistically adjusting for age. METHODS: An age-adjusted metanephrine score was derived using logistic regression from 343 subjects (including 33 people with pheochromocytoma) who underwent fractionated plasma metanephrine measurements as part of investigations for suspected pheochromocytoma at Mayo Clinic Rochester (derivation set). The performance of the age-adjusted score was validated in a dataset of 158 subjects (including patients 23 with pheochromocytoma) that underwent measurements of fractionated plasma metanephrines at Mayo Clinic the following year (validation dataset). None of the participants in the validation dataset had known genetic predisposition to pheochromocytoma. RESULTS: The sensitivity of the age-adjusted metanephrine score was the same as that of traditional interpretation of fractionated plasma metanephrine measurements, yielding a sensitivity of 100% (23/23, 95% confidence interval [CI] 85.7%, 100%). However, the false positive rate with traditional interpretation of fractionated plasma metanephrine measurements was 16.3% (22/135, 95% CI, 11.0%, 23.4%) and that of the age-adjusted score was significantly lower at 3.0% (4/135, 95% CI, 1.2%, 7.4%) (p < 0.001 using McNemar's test). CONCLUSION: An adjustment for age in the interpretation of results of fractionated plasma metanephrines may significantly decrease false positives when using this test to exclude sporadic pheochromocytoma. Such improvements in false positive rate may result in savings of expenditures related to confirmatory imaging

Critical Appraisal of Four IL-6 Immunoassays

BACKGROUND: Interleukin-6 (IL-6) contributes to numerous inflammatory, metabolic, and physiologic pathways of disease. We evaluated four IL-6 immunoassays in order to identify a reliable assay for studies of metabolic and physical function. Serial plasma samples from intravenous glucose tolerance tests (IVGTTs), with expected rises in IL-6 concentrations, were used to test the face validity of the various assays. METHODS AND FINDINGS: IVGTTs, administered to 14 subjects, were performed with a single infusion of glucose (0.3 g/kg body mass) at time zero, a single infusion of insulin (0.025 U/kg body mass) at 20 minutes, and frequent blood collection from time zero to 180 minutes for subsequent Il-6 measurement. The performance metrics of four IL-6 detection methods were compared: Meso Scale Discovery immunoassay (MSD), an Invitrogen Luminex bead-based multiplex panel (LX), an Invitrogen Ultrasensitive Luminex bead-based singleplex assay (ULX), and R&D High Sensitivity ELISA (R&D). IL-6 concentrations measured with MSD, R&D and ULX correlated with each other (Pearson Correlation Coefficients r = 0.47-0.94, p<0.0001) but only ULX correlated (r = 0.31, p = 0.0027) with Invitrogen Luminex. MSD, R&D, and ULX, but not LX, detected increases in IL-6 in response to glucose. All plasma samples were measurable by MSD, while 35%, 1%, and 4.3% of samples were out of range when measured by LX, ULX, and R&D, respectively. Based on representative data from the MSD assay, baseline plasma IL-6 (0.90 ± 0.48 pg/mL) increased significantly as expected by 90 minutes (1.29 ± 0.59 pg/mL, p = 0.049), and continued rising through 3 hours (4.25 ± 3.67 pg/mL, p = 0.0048). CONCLUSION: This study established the face validity of IL-6 measurement by MSD, R&D, and ULX but not LX, and the superiority of MSD with respect to dynamic range. Plasma IL-6 concentrations increase in response to glucose and insulin, consistent with both an early glucose-dependent response (detectable at 1-2 hours) and a late insulin-dependent response (detectable after 2 hours)