Parameter Estimation in Enzyme-Kinetics with Consideration of Heteroscedasticity and Low Dose Data

In this paper we propose a simulation study in order to discuss four statistical models dealing with the problem of parameter estimation in enzyme-kinetics. The pseudo-maximum-likelihood estimators for the transform-both-sides-model and the weighted TBS-model are compared with least-square-estimators of the classical nonlinear regression model and the linearized Eadie-Hofstee-plot. Due to heteroscedasticity of enzyme-kinetic data in low dose experiments the proposed estimators are investigated

Clinical and exploratory biomarker findings from the MODUL trial (Cohorts 1, 3 and 4) of biomarker-driven maintenance therapy for metastatic colorectal cancer

Biomarkers; Colorectal cancer; Maintenance therapyBiomarcadors; Càncer colorectal; Teràpia de mantenimentBiomarcadores; Cáncer colorrectal; Terapia de mantenimientoPurpose MODUL is an adaptable, signal-seeking trial of biomarker-driven maintenance therapy following first-line induction treatment in patients with metastatic colorectal cancer (mCRC). We report findings from Cohorts 1 (BRAFmut), 3 (human epidermal growth factor 2 [HER2]+) and 4 (HER2‒/high microsatellite instability, HER2‒/microsatellite stable [MSS]/BRAFwt or HER2‒/MSS/BRAFmut/RASmut). Methods Patients with unresectable, previously untreated mCRC without disease progression following standard induction treatment (5-fluorouracil/leucovorin [5-FU/LV] plus oxaliplatin plus bevacizumab) were randomly assigned to control (fluoropyrimidine plus bevacizumab) or cohort-specific experimental maintenance therapy (Cohort 1: vemurafenib plus cetuximab plus 5-FU/LV; Cohort 3: capecitabine plus trastuzumab plus pertuzumab; Cohort 4: cobimetinib plus atezolizumab). The primary efficacy end-point was progression-free survival (PFS). Results Cohorts 1, 3 and 4 did not reach target sample size because of early study closure. In Cohort 1 (n = 60), PFS did not differ between treatment arms (hazard ratio, 0.95; 95% confidence intervals 0.50–1.82; P = 0.872). However, Cohort 1 exploratory biomarker data showed preferential selection for mitogen-activated protein kinase (MAPK) pathway mutations (mainly KRAS, NRAS, MAP2K1 or BRAF) in the experimental arm but not the control arm. In Cohort 3 (n = 5), PFS ranged from 3.6 to 14.7 months versus 4.0 to 5.4 months in the experimental and control arms, respectively. In Cohort 4 (n = 99), PFS was shorter in the experimental arm (hazard ratio, 1.44; 95% confidence intervals 0.90–2.29; P = 0.128). Conclusions Vemurafenib plus cetuximab plus 5-FU/LV warrants further investigation as first-line maintenance treatment for BRAFmut mCRC. MAPK-pathway emergent genomic alterations may offer novel therapeutic opportunities in BRAFmut mCRC. Cobimetinib plus atezolizumab had an unfavourable benefit:risk ratio in HER2‒/MSS/BRAFwt mCRC. New strategies are required to increase the susceptibility of MSS mCRC to immunotherapy.This work was supported by F. Hoffmann-La Roche Ltd

Design of a study assessing disease behaviour during the peri-diagnostic period in patients with interstitial lung disease: The STARLINER Study

This study will aim to characterise disease behaviour during the peri-diagnostic period in patients with suspected interstitial lung disease (ILD), including idiopathic pulmonary fibrosis (IPF), using daily home spirometry and accelerometry. Additionally, this study will aim to increase collaboration between secondary and tertiary centres using a digital collaboration platform

Design of a Study Assessing Disease Behaviour During the Peri-Diagnostic Period in Patients with Interstitial Lung Disease: The STARLINER Study

Background/Objectives: This study will aim to characterise disease behaviour during the peri-diagnostic period in patients with suspected interstitial lung disease (ILD), including idiopathic pulmonary fibrosis (IPF), using daily home spirometry and accelerometry. Additionally, this study will aim to increase collaboration between secondary and tertiary centres using a digital collaboration platform. Methods: The STARLINER study (NCT03261037) will enrol approximately 180 symptomatic patients aged 50 years or more with radiological evidence of ILD/IPF from community and tertiary centres in Canada and Europe. Approximately two-thirds of sites will be community centres. Patients will be followed during pre-diagnosis (inclusion to diagnosis; up to a maximum of 12 months) and post-diagnosis (diagnosis to treatment initiation; up to a maximum of 6 months). The study will be facilitated by a digital ecosystem consisting of the devices used for home-based assessments and a digital collaboration platform enabling communication between community and tertiary centres, and between clinicians and patients. Planned Outcomes: The primary endpoint will be time-adjusted semi-annual change in forced vital capacity (FVC; in millilitres) during the peri-diagnostic period. Physical functional capacity and patient-reported outcomes (PROs) will also be assessed. FVC and physical functional capacity will be measured using daily home spirometry and accelerometry, and at site visits using spirometry and the 6-min walk test. PROs will be assessed prior to, or during, site visits and will always be completed in the same order. Conclusions: Findings from this study may help to facilitate the early and accurate diagnosis of ILDs by increasing knowledge about disease progression, enabling collaboration between community and tertiary centres and improving communication between clinicians and patients. Trial Registration Number: NCT03261037. Funding: F. Hoffmann-La Roche, Ltd., Basel, Switzerland. Plain Language Summary: Plain language summary available for this article

Evaluation der Maßnahmen zur Umsetzung der Vorschläge der Hartz-Kommission: Modul 1a, Neuausrichtung der Vermittlungsprozesse ; Bericht 2005 für das Bundesministerium für Wirtschaft und Arbeit

"Das Bundesministerium für Wirtschaft und Arbeit hat das Wissenschaftszentrum Berlin für Sozialforschung und das infas Institut für angewandte Sozialwissenschaft im September 2004 mit dem Evaluationsvorhaben Arbeitspaket 1, 'Modul 1a Neuausrichtung der Vermittlungsprozesse' beauftragt. Im Mittelpunkt steht die zentrale Frage, ob eine 'Verbesserung der Qualität und Schnelligkeit der Arbeitsvermittlung' nachgewiesen werden kann, die auf die Reformgesetze und -maßnahmen zurückzuführen sind. Implementationsanalysen untersuchen die Praxis der Agenturen bezüglich Bewerberdifferenzierung, Kundenmanagement, Aktivierung sowie Neuregelung von Zumutbarkeit und Sperrzeiten sowie die Vermittlungsdienstleistungen an Arbeitgeber. Auch der Einsatz vermittlungsnaher Dienstleistungen (Einschaltung Dritter nach Paragraph 37, Eingliederungsmaßnahmen durch Träger Paragraph 421i, Vermittlungsgutscheine, Personal-Service-Agenturen -PSA-) wird unter Umsetzungsgesichtspunkten untersucht. Über die Vermittlungsorganisation in Arbeitsgemeinschaften nach Paragraph 44b SGB II liegen erste Ergebnisse einer Grunderhebung vor. Die mittels Fallstudien, Dokumentenanalyse, schriftlichen und telefonischen Erhebungen gewonnenen Ergebnisse umreißen den Stand der Neuausrichtung der Vermittlungsprozesse. Die Wirkung der neu ausgerichteten Vermittlungsprozesse werden unter zwei Gesichtspunkten untersucht. Mittels multivariater Auswertungen wird zum einen die Wirkung des Kundenzentrums auf die Abgänge aus Arbeitslosigkeit geprüft. In einer instrumentenspezifisch angelegten Wirkungsanalyse wird zum anderen die Effektivität von vermittlungsnahen Dienstleistungen (Beauftragung Dritter, Beauftragung von Trägern mit Eingliederungsmaßnahmen, Personal Service Agenturen, Vermittlungsgutschein) analysiert und eine entsprechende Kosten-Nutzen-Bewertung vorgenommen. Der Bericht 2005 legt die Ergebnisse nach neun Monaten Laufzeit des Evaluationsvorhabens vor. Er ist vom Bemühen getragen, bereits belastbare Ergebnisse nach diesem vergleichsweise kurzen Zeitraum vorzulegen. Die Berichterstattung steht allerdings unter dem deutlichen Hinweis, dass die Organisation der Vermittlungsprozesse in den Agenturen und Arbeitsgemeinschaften weiterhin im Fluss ist. Die Implementationsstudien versuchen deswegen über die Momentaufnahme hinaus, grundlegende Konstruktionsfragen und -probleme aufzuzeigen. Wegen des vergleichsweise kurzen Beobachtungszeitraums seit Einführung der Kundenzentren und der vermittlungsnahen Dienstleistungen stehen auch die Wirkungsanalysen noch unter Vorbehalten." (Textauszug

Safety of nintedanib added to pirfenidone treatment for idiopathic pulmonary fibrosis

We assessed safety and tolerability of treatment with pirfenidone (1602-2403 mg day-1) and nintedanib (200-300 mg day-1) in patients with idiopathic pulmonary fibrosis (IPF). This 24-week, single-arm, open-label, phase IV study (ClinicalTrials.gov identifier NCT02598193) enrolled patients with IPF with forced vital capacity % pred ≫50% and diffusing capacity of the lung for carbon monoxide % pred ≫30%. Before initiating nintedanib, patients had received pirfenidone for ≫16 weeks and tolerated a stable dose of ≫1602 mg day-1 for ≫28 days. The primary end-point was the proportion of patients who completed 24 weeks of combination treatment on pirfenidone (1602- 2403 mg day-1) and nintedanib (200-300 mg day-1). Investigators recorded treatment-emergent adverse events (TEAEs), attributing them to pirfenidone, nintedanib, both or neither. 89 patients were enrolled; 73 completed 24 weeks of treatment (69 meeting the primary end-point) and 16 discontinued treatment prematurely (13 due to TEAEs). 74 patients had 418 treatment-related TEAEs, of which diarrhoea, nausea and vomiting were the most common. Two patients had serious treatmentrelated TEAEs. Combined pirfenidone and nintedanib use for 24 weeks was tolerated by the majority of patients with IPF and associated with a similar pattern of TEAEs expected for either treatment alone. These results encourage further study of combination treatment with pirfenidone and nintedanib in patients with IPF

Heteroscedastic nonlinear regression models with random effects

We discuss an extansion of the nonlinear random effects model from Lindstrom and Bates (1990) by adding a flexible transformation to both sides of the model (see Carroll and Ruppert (1988)) and describe a procedure for parameter estimation. This method combines pseudo maximum likelihood estimators for the transform-both-sides and weighting model and maximum likelihood (or restricted maximum likelihood) estimatiors for the linear mixed effects models. A validation of this new method is performed by analyzing a simulated set of enzyme kinetic data published by Jones (1993)