A Framework for Design of Two-Stage Adaptive Procedures

The main objective of this dissertation is to introduce a framework for two-stage adaptive procedures in which the blind is broken at the end of Stage I. Using our framework, it is possible to control many aspects of an experiment including the Type I error rate, power and maximum total sample size. Our framework also enables us to compare different procedures under the same formulation. We conduct an ANOVA type study to learn the effects of different components of the design specification on the performance characteristics of the resulting design. In addition, we consider conditions for the monotonicity of the power function of a two-stage adaptive procedure.To foster the practicality of our framework, two extensions are considered. The first one is an application of our framework to the settings with unequal sample sizes. We show how to design a two-stage adaptive procedure having unequal sample sizes for the treatment and control groups. Also we illustrate how to modify an ongoing two-stage adaptive trial when some observations are missing in Stage I and/or in Stage II. Second, we extend the framework to unknown population variance. Our framework can construct a design that incorporates updating the variance estimate at the end of Stage I and modifies the design of Stage II accordingly. All the procedures we present protect the Type I error rate and allow specification of the power and the maximum sample size.We also consider the problem of switching design objectives between testing noninferiority and testing superiority. Our framework can be used to design a two-stage adaptive procedure that simultaneously tests both noninferiority and superiority hypotheses with controlled error probabilities. The sample size for Stage I is chosen for the main study objective, but that objective may be switched for Stage II based on the unblinded observations from Stage I. Our framework offers a technique to specify certain design criteria such as the various Type I error rates, power and maximum sample sizes

A Bayesian Approach for the Cox Proportional Hazards Model with Covariates Subject to Detection Limit

The research on biomarkers has been limited in its effectiveness because biomarker levels can only be measured within the thresholds of assays and laboratory instruments, a challenge referred to as a detection limit (DL) problem. In this paper, we propose a Bayesian approach to the Cox proportional hazards model with explanatory variables subject to lower, upper, or interval DLs. We demonstrate that by formulating the time-to-event outcome using the Poisson density with counting process notation, implementing the proposed approach in the OpenBUGS and JAGS is straightforward. We have conducted extensive simulations to compare the proposed Bayesian approach to the other four commonly used methods and to evaluate its robustness with respect to the distribution assumption of the biomarkers. The proposed Bayesian approach and other methods were applied to an acute lung injury study, in which a panel of cytokine biomarkers was studied for the biomarkers' association with ventilation-free survival

Effect of temperature on thermophilic composting of aquaculture sludge: NH3 recovery, nitrogen mass balance, and microbial community dynamics

Development of thermophilic composting for maximizing NH3 gas recovery would enable the production of a nitrogen source which is free from pathogen/heavy metal, for the cultivation of high-value microalgae. The present study examined the effect of NH3 recovery, nitrogen mass balance, and microbial community dynamics on thermophilic composting of shrimp aquaculture sludge. The emission of NH3 gas at 60 and 70 °C was 14.7% and 15.6%, respectively, which was higher than that at 50 °C (9.0%). The nitrogen mass balance analysis revealed that higher temperatures enhanced the solubilization of non-dissolved nitrogen and liberation of NH3 gas from the produced NH4+-N. High-throughput microbial community analysis revealed the shift of the dominant bacterial group from Bacillus to Geobacillus with the rise of composting temperature. In conclusion, thermophilic composting of shrimp aquaculture sludge at 60–70 °C was the most favorable condition for enhancing NH3 gas recovery

Enhancing Cancer Care of Rural Dwellers through Telehealth and Engagement (ENCORE): Protocol to Evaluate Effectiveness of a Multi-Level Telehealth-Based Intervention to Improve Rural Cancer Care Delivery

BACKGROUND: Despite lower cancer incidence rates, cancer mortality is higher among rural compared to urban dwellers. Patient, provider, and institutional level factors contribute to these disparities. The overarching objective of this study is to leverage the multidisciplinary, multispecialty oncology team from an academic cancer center in order to provide comprehensive cancer care at both the patient and provider levels in rural healthcare centers. Our specific aims are to: 1) evaluate the clinical effectiveness of a multi-level telehealth-based intervention consisting of provider access to molecular tumor board expertise along with patient access to a supportive care intervention to improve cancer care delivery; and 2) identify the facilitators and barriers to future larger scale dissemination and implementation of the multi-level intervention. METHODS: Coordinated by a National Cancer Institute-designated comprehensive cancer center, this study will include providers and patients across several clinics in two large healthcare systems serving rural communities. Using a telehealth-based molecular tumor board, sequencing results are reviewed, predictive and prognostic markers are discussed, and treatment plans are formulated between expert oncologists and rural providers. Simultaneously, the rural patients will be randomized to receive an evidence-based 6-week self-management supportive care program, Cancer Thriving and Surviving, versus an education attention control. Primary outcomes will be provider uptake of the molecular tumor board recommendation and patient treatment adherence. A mixed methods approach guided by the Consolidated Framework for Implementation Research that combines qualitative key informant interviews and quantitative surveys will be collected from both the patient and provider in order to identify facilitators and barriers to implementing the multi-level intervention. DISCUSSION: The proposed study will leverage information technology-enabled, team-based care delivery models in order to deliver comprehensive, coordinated, and high-quality cancer care to rural and/or underserved populations. Simultaneous attention to institutional, provider, and patient level barriers to quality care will afford the opportunity for us to broadly share oncology expertise and develop dissemination and implementation strategies that will enhance the cancer care delivered to patients residing within underserved rural communities. TRIAL REGISTRATION: Clinicaltrials.gov , NCT04758338 . Registered 17 February 2021 - Retrospectively registered, http://www.clinicaltrials.gov/

Androgen Regulated Genes in Human Prostate Xenografts in Mice: Relation to BPH and Prostate Cancer

Benign prostatic hyperplasia (BPH) and prostate carcinoma (CaP) are linked to aging and the presence of androgens, suggesting that androgen regulated genes play a major role in these common diseases. Androgen regulation of prostate growth and development depends on the presence of intact epithelial-stromal interactions. Further, the prostatic stroma is implicated in BPH. This suggests that epithelial cell lines are inadequate to identify androgen regulated genes that could contribute to BPH and CaP and which could serve as potential clinical biomarkers. In this study, we used a human prostate xenograft model to define a profile of genes regulated in vivo by androgens, with an emphasis on identifying candidate biomarkers. Benign transition zone (TZ) human prostate tissue from radical prostatectomies was grafted to the sub-renal capsule site of intact or castrated male immunodeficient mice, followed by the removal or addition of androgens, respectively. Microarray analysis of RNA from these tissues was used to identify genes that were; 1) highly expressed in prostate, 2) had significant expression changes in response to androgens, and, 3) encode extracellular proteins. A total of 95 genes meeting these criteria were selected for analysis and validation of expression in patient prostate tissues using quantitative real-time PCR. Expression levels of these genes were measured in pooled RNAs from human prostate tissues with varying severity of BPH pathologic changes and CaP of varying Gleason score. A number of androgen regulated genes were identified. Additionally, a subset of these genes were over-expressed in RNA from clinical BPH tissues, and the levels of many were found to correlate with disease status. Our results demonstrate the feasibility, and some of the problems, of using a mouse xenograft model to characterize the androgen regulated expression profiles of intact human prostate tissues

Guidelines for reporting of statistics for clinical research in urology

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/148242/1/bju14640.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/148242/2/bju14640_am.pd

Peer Review Model Kepemimpinan Modern di Program Pascasarjana Universitas Ahmad Dahlan

Logistic regression model for in-hospital mortality in patients without head injury. (DOCX 14 kb

RUNX1 transactivates BCR-ABL1 expression in Philadelphia chromosome positive acute lymphoblastic leukemia

The emergence of tyrosine kinase inhibitors as part of a front-line treatment has greatly improved the clinical outcome of the patients with Ph⁺ acute lymphoblastic leukemia (ALL). However, a portion of them still become refractory to the therapy mainly through acquiring mutations in the BCR-ABL1 gene, necessitating a novel strategy to treat tyrosine kinase inhibitor (TKI)-resistant Ph⁺ ALL cases. In this report, we show evidence that RUNX1 transcription factor stringently controls the expression of BCR-ABL1, which can strategically be targeted by our novel RUNX inhibitor, Chb-M'. Through a series of in vitro experiments, we identified that RUNX1 binds to the promoter of BCR and directly transactivates BCR-ABL1 expression in Ph⁺ ALL cell lines. These cells showed significantly reduced expression of BCR-ABL1 with suppressed proliferation upon RUNX1 knockdown. Moreover, treatment with Chb-M' consistently downregulated the expression of BCR-ABL1 in these cells and this drug was highly effective even in an imatinib-resistant Ph⁺ ALL cell line. In good agreement with these findings, forced expression of BCR-ABL1 in these cells conferred relative resistance to Chb-M'. In addition, in vivo experiments with the Ph⁺ ALL patient-derived xenograft cells showed similar results. In summary, targeting RUNX1 therapeutically in Ph⁺ ALL cells may lead to overcoming TKI resistance through the transcriptional regulation of BCR-ABL1. Chb-M' could be a novel drug for patients with TKI-resistant refractory Ph⁺ ALL

Search for eccentric black hole coalescences during the third observing run of LIGO and Virgo

Despite the growing number of confident binary black hole coalescences observed through gravitational waves so far, the astrophysical origin of these binaries remains uncertain. Orbital eccentricity is one of the clearest tracers of binary formation channels. Identifying binary eccentricity, however, remains challenging due to the limited availability of gravitational waveforms that include effects of eccentricity. Here, we present observational results for a waveform-independent search sensitive to eccentric black hole coalescences, covering the third observing run (O3) of the LIGO and Virgo detectors. We identified no new high-significance candidates beyond those that were already identified with searches focusing on quasi-circular binaries. We determine the sensitivity of our search to high-mass (total mass M>70 M⊙) binaries covering eccentricities up to 0.3 at 15 Hz orbital frequency, and use this to compare model predictions to search results. Assuming all detections are indeed quasi-circular, for our fiducial population model, we place an upper limit for the merger rate density of high-mass binaries with eccentricities 0<e≤0.3 at 0.33 Gpc−3 yr−1 at 90\% confidence level