Diss. (sammanfattning) Linköping : Univ., 2001. / Härtill 5 uppsatser.

Diss. (sammanfattning) Stockholm : Univ., 2004. / Härtill 4 uppsatser.

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As most adaptive clinical trial designs are implemented in stages, well-understood methods of sequential trial monitoring are needed. In the frequentist paradigm, examples of sequential monitoring methodologies include the p-value combination tests, conditional error, conditional power, and alpha spending approaches. Within the Bayesian framework, posterior and predictive probabilities are used as monitoring criteria, with the latter being analogous to the conditional power approach. In a placebo or active-contolled dose response clinical trial, we are interested in achieving two objectives: selecting the best therapeutic dose and confirming this selected dose. Traditional approach uses the parallel group design with Dunnett's adjustment. Recently, some two- stage Seamless II/III designs have been proposed. The drop-the-losers design considers selecting the dose with the highest empirical mean after the first stage, while another design assumes a dose-response model to aid dose selection. These designs however do not consider prioritizing the doses and adaptively inserting new doses. We propose an adaptive staggered dose design for a normal endpoint that makes minimal assumption regarding the dose response and sequentially adds doses to the trial. An alpha spending function is applied in a novel way to monitor the doses across the trial. Through numerical and simulation studies, we confirm that optimistic alpha spending coupled with informative dose ordering jointly produce some desirable operating characteristics when compared to drop-the-losers and model-based Seamless designs. In addition, we show how the design parameters can be flexibly varied to further improve its performance and how it can be extended to binary and survival endpoints. In a biosimilarity trial, we are interested in establishing evidence of comparable efficacy between a follow-on biological product and a reference innovator product. So far, no standard method for biosimilarity has been endorsed by regulatory agency. We propose a Bayesian hierarchical bias model and a non-inferiority hypothesis framework to prove biosimilarity. A two-stage adaptive design using predictive probability as early stopping criterion is pro- posed. Through simulation study, the proposed design controls the type I error better than the frequentist approach and Bayesian power is superior when biosimilarity is plausible. Two-stage design further reduces the expected sample size.

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The ability to generate a range of concentrations of various solutions rapidly and conveniently is an ongoing need in biotechnology. In this thesis we demonstrate how we took advantage of the full process control afforded by our recent custom high resolution 3D printer and resin advances to realize highly integrated and miniaturized microfluidic components for simultaneous on-chip serial dilution for dose-response assays. With judicious selection of mixed layer thicknesses and pixel-by-pixel dose control, we show that the diameter of 3D printed membrane valves can be reduced from 300 µm to 46 µm. We further introduce an entirely new kind of 3D printed valve, termed a squeeze valve, in which the active area is reduced still further to 15 µm x 15 µm. We demonstrate and characterize pumps based on each type of valve and introduce a short (<1 mm long) high aspect ratio channel that enables rapid diffusion-based mixing. We show that combining two pumps with this diffusion mixing channel results in a highly compact 1:1 mixer component. Connecting 10 of these components in series yields a miniature 10 stage 2-fold microfluidic serial dilution module that from two solution inputs simultaneously generates 10 output concentrations that cover three orders of magnitude. We show the efficacy of our serial dilution approach by demonstrating an assay for dose-dependent permeabilization of A549 cells in different concentrations of digitonin integrated into a single device. Our demonstration of component miniaturization in conjunction with a high degree of integration illustrates the promise of 3D printing to enable highly functional and compact microfluidic devices for a variety of biomolecular applications.

Athlete preparation and performance continue to increase in complexity and costs. Modern coaches are shifting from reliance on personal memory, experience, and opinion to evidence from collected training-load data. Training-load monitoring may hold vital information for developing systems of monitoring that follow the training process with such precision that both performance prediction and day-to-day management of training become adjuncts to preparation and performance. Time-series data collection and analyses in sport are still in their infancy, with considerable efforts being applied in "big data" analytics, models of the appropriate variables to monitor, and methods for doing so. Training monitoring has already garnered important applications but lacks a theoretical framework from which to develop further. As such, we propose a framework involving the following: analyses of individuals, trend analyses, rules-based analysis, and statistical process control.

The dose-effect relationship in psychotherapy has been examined extensively, but few studies have included session frequency as a component of psychotherapy "dose." Those studies that have examined the effects of session frequency have indicated that it may affect both the total amount of recovery and the speed of recovery. No studies were found examining the clinical significance of this construct in a naturalistic setting. The change trajectories of 16,003 clients were examined using multi-level modeling and including session frequency as a fixed effect. Of these clients, subgroups were identified that were scheduled approximately once a week or approximately once every two weeks. These groups were compared to each other for differences in speed of recovery and clinically significant change. Results indicated that more frequent therapy was associated with steeper recovery curves. When comparing groups scheduled once a week to those scheduled once every two weeks, more clinically significant gains were identified in those attending once a week, and more significant deterioration was identified in those attending once every two weeks. These findings are discussed in light of the existing literature and the implications for future psychotherapy research and clinical practice.

The objectives of this dissertation include 1) to review athlete monitoring strategies and the physical performance demands of female soccer match-play and to provide practical application of athlete monitoring programs, 2) to examine individual and group relationship between training load (TL) and subjective recovery and stress state and neuromuscular performance, and 3) to investigate acute effects of match-play on neuromuscular and subjective recovery and stress state in National Collegiate Association Athlete (NCAA) division I collegiate female soccer. TL was assessed using 10Hz Global Navigation Satellite System units. Subjective recovery and stress state was measured using the Short Recovery and Stress Scale (SRSS) consisting of 8 subscales including Physical Performance Capability (PPC) Mental Performance Capability (MPC), Emotional Balance (EB), Overall Recovery (OR), Muscular Stress (MS), Lack of Activation (LA), Negative Emotional State (NES), and Overall Stress (OS). Neuromuscular performance was assessed using countermovement jump (CMJ) with a polyvinyl chloride pipe (CMJ0) and 20kgs bar (CMJ20). CMJ variables included body mass (BdM), jump height (JH), modified reactive strength index (RSI), peak force (PF), relative peak force (RPP), eccentric impulse (EI), concentric impulse (CI), peak power (PP), relative peak power (RPP), eccentric average peak power (EAP), and concentric average power (CAP). Results of this dissertation showed that 12 individual players demonstrated negative correlations between total distance and MPC (p≤0.05, r=-0.78 to -0.34, number of significant individual correlations [N]=3) and OR (p≤0.05, r=-0.91 to -0.08, N=3). Positive correlations were observed between MS and total distance among all individual players (p≤0.05, r=0.21 to 0.82, N=3) while the group correlations were moderate to large (p≤0.001, r=0.55). Results of this dissertation also demonstrated that significant moderate to large decreases were observed at 12 hours post-match in JH, RSI, CI, PP, RPP, and CPA in CMJ0 and CMJ20 (p