Restricted classification and similarity rating tasks employing the dimensions of line length and density were used to investigate several issues. One of these was developmental differences in the overall separability of those dimensions. The contribution of perceptual limitation and strategic factors to levels of dimensional responding and to developmental changes in that responding were also investigated. Finally, changes in levels of dimensional responding across trials with simuli and the contribution of those changes to observed developmental differences were studied. Adults (college students) gave more dimensional responses than did children (4 to 6 year olds) and tended to give more dimensional classifications than other type of response.

Background Surrogate outcomes are measures of treatment effect that can be used to predict treatment effect on the true outcome of interest. Surrogates are valued as they can be used in place of true outcomes to reduce the length, size, or intrusiveness of a clinical trial. However, validation of surrogacy is a conceptually complicated area and much theoretical and practical statistical development has been conducted in recent years. Methods A systematic review was conducted to identify which surrogate evaluation approach was best suited to be extended to ordinal outcomes. I extended a foremost approach to the case where the surrogate, the true clinical outcome, or both are ordinal outcomes. This extension investigated surrogacy at both the trial and individual levels; trial level surrogacy was based on a two stage method. The extension was developed through large simulation studies and used to investigate whether deep venous thromboembolism (DVT) was a surrogate for the ongoing measure of death and disability the Oxford Handicap Scale (OHS), using data from the stroke trial CLOTS3. CLOTS3 was a large multi-centre randomised clinical trial which investigated whether intermittent pneumatic compression (IPC) applied to the legs reduced the occurrence of deep venous thromboembolism (DVT) in stroke clinical trial patients. Results The systematic review identified the information theory approach as the most intuitively and practically worthwhile approach to surrogacy evaluation. I extended this approach to: a binary surrogate and ordinal true outcome (the binary-ordinal setting); the ordinal-binary and the ordinal-ordinal settings. The simulation studies showed that the approach worked well in most scenarios tested. However, trial level surrogacy was impacted by loss of efficiency due to the use of the two stage method. Bias imposed at the trial level by separation of discrete outcomes was effectively dealt with using a penalised likelihood method. The information theory approach for ordinal outcomes identified no surrogate that would predict treatment effect of IPC on the true outcome OHS measured at six months in the stroke trial CLOTS3.

The pharmaceutical industry is currently facing an industry wide problem of high attrition rates for new compounds and rising development costs. As a result of this, there is an emphasis on making the development process more ecient. By learning more about new compounds in the early stages of development, the aim is to stop ineective compounds earlier and improve dose selection for compounds that progress to phase III. One approach to this is to use adaptive designs. The focus of this thesis is on response adaptive designs within phase IIb dose-finding studies. We explore adapting the subject allocations based on accrued data, with the intention of focusing the allocation on the interesting parts of the curve and/or the best dose for phase III. In this thesis we have used simulation studies to assess the operational characteristics of a number of response adaptive designs. We found that there were consistent gains to be made by adapting when we were relatively cautious in our method of adaptation. That is, the adaptive method has the opportunity to alter the subject allocation when there is a clear signal in the data, but maintains roughly equal allocation when there is a lot of variability in the data. When we used adaptive designs that were geared to randomising subjects to a few doses, the results were more varied. In some cases the adaptation led to gains in efficacy whilst in others it was detrimental. One of the key aims of a phase IIb dose-finding study is to identify a dose to take forward into phase III. In the final chapter, we show that the way in which we choose the dose for phase III affects the expected gain, and so begin to consider how we can optimise the decision making process.

Class of 2007 Abstract / Objectives: In this paper we analyzed the time frame for oncology drugs that were designated as a fast track drug and the time transition from a phase II to phase III clinical trial completion. Methods In our study we utilized oncology drugs that were approved between the years of 2000-2006 (FDA.gov). We then analyzed the CDER data base that provided information to Fast Track drugs that have been approved within the time period as determined by the FDA selection criteria (21 CFR 312.81(a)). Under certain circumstances, the FCA may consider reviewing portions of a marketing application in advance of the complete New Drug Application (NDA) or Biologic License Application (BLA). We will evaluate fast track designated products which may also be eligible to participate in FDA’s Continuous Marketing Applications Pilot 1 or Pilot 2 programs. For our analysis, we specifically selected oncology drugs. In particular, we analyzed 32 drugs from the stated time period. Each fast track drug was then selected and analyzed for its clinical phase development time period based on news announcements during clinical trails. For each announcement we conducted an event study analysis through lexis Nexus with respect to the announcement of a clinical trial enrollment, clinical trials news (Phase I, II, III). Results: The results of our preliminary study show that there was a shorter time to development transition for the fast track oncology drugs. The oncology clinical phase transition from II to three on average lasted 12 months with a range of 2 - 29 months The average length of the phase development had to excludes 4 drugs due to the lack of information provided from the LexisNexis database. The current timeline for fats track drugs has shown a decrease in transition from clinical trials to the market. In the example of Spyrcel, the data from our study had to be excluded, there was a definitive difference in the time to approval process for the drug as compared to other standard review entities. The approvals for dasatinib, or Sprycel, for refractory CML was shown to move through the development to approval in one of the fastest timeframes in modern development. Since its first clinical study on in Gleevec-resistant patients, the medication was decided on entering an accelerated timeline. It took us just 25 months to bring Sprycel from first-in-human dosing to a regulatory submission. In contrast, the industry average for this cycle time is 6.4 years which is three times greater than the cycle time for Sprycel. Conclusions: The new Subpart H regulations state that post-marketing studies to confirm clinical benefit that would consist usually by "studies underway” at the time of accelerated approval, this has not always been the case and is not a requirement (Dagher R, Johnson J, Williams G et al). In conclusion, the accelerated approval program in oncology has been successful in making 18 different products available to patients for 22 different cancer treatment indications since the inception of the fast track program. From the current data and transition information, there is a comparative difference between the clinical phase transitions from phase II to Phase III clinical trials. However, this preliminary data needs to be further evaluated against the standard FDA review process from oncology drugs. Moreover, further studies will be needed to interpret whether the average length of oncology studies biases the value of our study.

Wheat is one of the major crops of Utah and for more than 50 years farmers have been raising wheat on the dry lands of the state. The system they use is known as the alternate cropping or crop-follow system and consists of one year of crop alternating with one year of clean cultivation known as fallow. Wheat removes a considerable amount of the natural plant food elements from the soil each year. This is especially true of nitrogen. According to Bracken and Greaves (9) the original low supply of nitrogen in most Utah soils together with the depleting effects of alternate wheat and fallow has the possibility of making nitrogen rather than moisture the limiting factor of crop production in certain dry-farm areas. The amount of nitrogen removed from the soil by the wheat crop is only a portion of the total supply. Such factors as leaching to a lower depth beyond the feeding range of the plant, erosion, denitrification, and volatilization through biological and possibly chemical action are thought to be responsible for the loss of nitrogen unaccounted for by crop removal. The results of several investigators indicate that this loss is approximately twice as much as was removed by the crop. Since nitrogen is one of the major factors responsible for high yields and high quality of wheat, it naturally follows that any reduction of the amount of nitrogen in the soil produces a corresponding reduction in yield and quality of wheat. Recent reports show that this condition exists in Utah as well as in other areas. As a result of this reduction in yield and quality of wheat, processors are concerned about the problems. The seriousness of the problem cannot be over-emphasized. Ways and means of checking these losses and subsequently increasing the yield and quality are being studied. Three possible procedures for increasing soil nitrogen have been suggested: 1. the use of legumes, especially alfalfa, in a rotation program; 2. non-symbiotic nitrogen fixation: and 3. the use of commercial fertilizers. Since legumes have not been grown to any great extent, the only other natural source of nitrogen has been non-symbiotic fixation. Evidence in this field of investigation, however, indicates that this source is inadequate and that other sources must be bad. Also, the data indicate that no effective methods have been found which increase non-symbiotic fixation. Limited information suggests that further study is needed on the use of legumes for increasing the nitrogen and organic matter content of dry farm soils. This investigation is confined to the use of commercial fertilizers as one solution to the general problem.

PhD / Abstract Low back pain is a significant public health problem in many countries of the world being one of the major causes of work absence and disability. Although the outlook for evidence-based management of low back pain has greatly improved over the past decades, many questions remain. Questions related to treatment options, underlying mechanisms of treatment effects and optimal assessment of low back pain have yet to be fully addressed by researchers. The broad aim of this thesis therefore was to contribute to a better understanding of the contemporary management of low back pain by performing studies in these key research areas. Most clinical practice guidelines recommend exercise as an effective treatment option for chronic low back pain. However the evidence for this recommendation comes from trials that are not placebo-controlled and so this may potentially provide biased estimates of the effects of exercise. Therefore a randomised controlled trial testing the effect of motor control exercise versus placebo in patients with chronic low back pain was conducted. Chapters 2 and 3 describe the trial protocol and the report of the trial respectively. A total of 154 patients with chronic low back pain were randomised to receive a motor control exercise program, or placebo (i.e. detuned short-wave therapy and detuned ultrasound therapy). Primary outcomes were pain, function, and the patient’s global impression of recovery measured at 2 months. The exercise intervention improved function and patient’s global impression of recovery, but not pain, at 2 months. The mean effect of exercise on function was 1.1 points (95%CI, 0.3 to 1.8), the mean effect on global impression of recovery was 1.5 points (95%CI, 0.4 to 2.5) and the mean effect on pain was 0.9 points (95%CI, - 0.01 to 1.8), all measured on 11 point scales. Secondary outcomes also favoured motor control exercise. This is the first study ever to demonstrate that motor control exercise is better than placebo for patients with chronic low back pain. Most of the treatment effects were maintained at 6 and 12 months follow-up. These results suggest that this intervention should be considered for patients with chronic low back pain in order to improve disability, function, and global impression of recovery, and to improve pain intensity in the long term, but not in the short term. Rehabilitative ultrasound imaging (RUSI) has been increasingly used by physiotherapists in order to identify impairments in motor control as well as to monitor progress of patients with low back pain. As with any other clinical measure it is important to know how reproducible the RUSI measures are, and although there are some reproducibility studies in the literature, no systematic review on this topic has been conducted. Therefore a systematic review was performed with the objective of assessing the reproducibility studies of RUSI for abdominal wall muscles (Chapter 4). Eligible studies were indentified via searches in CINAHL, EMBASE and MEDLINE with citation tracking via the Web of Science Index. A total of 21 studies were included. Due to heterogeneity of the studies’ designs, pooling the data for a meta-analysis was not possible. RUSI measures of thickness of abdominal wall muscles were found to be reliable. Few studies analysed the reliability for the measurement of thickness changes (reflecting the muscle activity) finding good to poor results. Evidence for the reproducibility of the difference in thickness changes over time (necessary to evaluate improvements in muscle activity with treatment) was not available. A limitation of the existing literature is that studies typically had suboptimal designs and analysis. The current evidence for the reproducibility of RUSI for measuring abdominal muscle activity is mainly based upon studies with suboptimal designs that included mostly healthy subjects, making generalisability to clinical settings uncertain. Some questions about the reproducibility of RUSI measures of abdominal wall muscles are still unanswered; this is mainly due to design issues, such as inadequate statistics, inadequate sampling and lack of control of sources of bias (e.g. blinding and absence of controlling for ordering effects). In addition the clinically important questions about the reproducibility of thickness changes (reflecting the muscle activity) and differences in thickness changes over time (reflecting the improvement or deterioration of muscle activity) have not been adequately investigated. Therefore a reproducibility study that aimed to answer these questions was performed (Chapter 5). Thirty-five patients seeking care for chronic low back pain participated in this study. RUSI measures were taken at baseline and eight weeks post-baseline. Replicate measures of thickness, thickness changes and differences in thickness changes over time were analysed. The reproducibility of static images (thickness) was excellent (ICC2,1 = 0.97, 95%CI = 0.96-0.97, Standard Error of the Measurement (SEM) = 0.04cm, Smallest Detectable Change (SDC) = 0.11cm), the reproducibility of thickness changes was moderate (ICC2,1 = 0.72, 95%CI 0.65-0.76 SEM = 15%, SDC 41%), while the reproducibility of differences in thickness changes over time was poor. Improvements in the test protocol should be undertaken in order to enhance the reproducibility of RUSI measures, especially for differences in thickness chang over time. Self-report outcome measures (questionnaires) are widely used by health care providers for measuring patient’s health status or treatment outcomes. Most of the questionnaires related to low back pain were developed in English and therefore their usefulness in non-English speaking countries is considerably limited. Cross-cultural adaptation and clinimetric testing are possibly the most efficient methods for solving this problem. Although there are many publications on the topic, a simple guide on how to perform a cross-cultural adaptation and clinimetric testing was not available. Therefore a “clinician-friendly” narrative review for Brazilian physical therapists (Chapter 6) was written. This review aimed firstly to explain the concepts and the relevance of cross-cultural adaptation and clinimetrics testing, secondly to summarise the current guidelines on the topic, thirdly to provide advice on how to choose a relevant questionnaire and finally how to evaluate the quality of an adapted questionnaire. Some examples of cross-cultural adaptations and clinimetrics testing of relevant low back pain questionnaires in the Brazilian-Portuguese language were also provided. Although the number of international versions of low back questionnaires is growing, to date it is unclear which questionnaires have been cross-culturally adapted and into which specific language. To answer these questions a systematic review was conducted in order to describe the available cross-cultural adaptations of low back pain self-report outcome measures and the clinimetric testing that has occurred for each adaptation (Chapter 7). Searches were performed in MEDLINE, EMBASE, CINALH and LILACS; these searches were supplemented with information from experts in the field of low back pain from 27 different countries to ensure that the results were comprehensive. Sixty-one adaptations were identified. While there are a large number of low back pain questionnaires available, very few have been adapted into other languages, particularly commonly spoken languages such as Mandarin, Hindi and Portuguese. The quality and comprehensiveness of clinimetric testing varied considerably, with the evaluation of reliability and construct validity most common. Further cross-cultural adaptation and clinimetric studies are clearly needed and special consideration must be given to study designs for clinimetric testing. The final aim of this thesis was to cross-culturally adapt self-report instruments relevant to the management of low back pain in Brazil. This was achieved by two independent studies. The first study (Chapter 8) aimed to cross-culturally adapt the Functional Rating Index (FRI) into Brazilian-Portuguese and to test the clinimetric properties of the FRI and also of an existing Brazilian-Portuguese version of the Roland Morris Disability Questionnaire (RMDQ) which was not fully evaluated in the original study. Both instruments were tested for internal consistency, reliability, construct validity, ceiling and floor effects and internal responsiveness in 140 chronic low back patients presenting for physiotherapy treatment in Brazil. Both instruments were considered reliable and valid for the measurement of disability in Brazilian-Portuguese speakers with low back pain, no ceiling or floor effects were detected, but the internal responsiveness of both instruments was considered small. The second study (Chapter 9) aimed to cross-culturally adapt the Patient-Specific Functional Scale (PSFS) and to perform a head-to-head comparison of the clinimetric properties of the PSFS, RMDQ and FRI. All instruments were tested for internal consistency, reliability, construct validity, ceiling and floor effects, internal and external responsiveness in 99 acute low back patients presenting for physiotherapy treatment in Brazil. In order to fully test the construct validity and external responsiveness, it was necessary to cross-culturally adapt the Pain Numerical Rating Scale and the Global Perceived Effect Scale. The results of this study demonstrate that the Brazilian-Portuguese versions of the RMDQ, FRI and PSFS have similar clinimetric properties to each other and to the original English versions; however the PSFS was the most responsive instrument. The results from the studies in Chapters 8 and 9 will benefit the understanding of low back pain by enabling international comparisons between studies conducted in Brazil and English speaking countries. In addition it will encourage researchers to include Brazilian- Portuguese speakers in their future clinical trials. Overall, the studies included in this thesis have provided an important contribution to the contemporary management of low back pain. Firstly the use of motor control exercise could be considered for patients with chronic low back pain as it produces improvements in global impression of recovery, function, disability and pain. Secondly RUSI measures of abdominal wall muscles in patients with low back pain were considered reproducible for the measurement of muscle activity, but not as an outcome measure to detect improvement/deterioration of muscle activity over the course of treatment. Thirdly just a few high-quality cross-cultural adaptations and clinimetrics testing for self-report outcome measures relevant to the management of low back pain are available, and clearly more studies in this area are needed. Finally the Brazilian-Portuguese versions of the Functional Rating Index, the Roland Morris Disability Questionnaire and the Patient-Specific Functional Scale have acceptable clinimetric properties and could be used in clinical practice as well as in research studies in Brazil.

Discrete-trials teaching (DTT) is one of the principal techniques used in Applied Behaviour Analysis programs for children with autism. Although the demand for training individuals to implement DTT is high, published studies on strategies to do so are few. I conducted two experiments to investigate a training package for teaching individuals to implement DTT. In Experiment 1, I used a modified multiple-baseline design to evaluate the training package for teaching five university students to implement DTT to teach three tasks to a confederate role-playing a child with autism. Also, in an AB within-subject design with each participant, I compared two components of the training package, a Self-Instructional Manual and Feedback plus Demonstration. Experiment 2 was a systematic replication of Experiment 1, with 2 teaching assistants, a resource teacher, and 3 parents of children with autism as participants. In both experiments I assessed the generalization (G1) of participants’ ability to implement DTT (while teaching the confederate) to teach tasks not targeted for Feedback plus Demonstration, as well as generalization (G2) of DTT while teaching a child with autism. After an average of approximately 3 hours to master the self-instructional manual, participants’ DTT accuracy in both experiments improved from an average of 34% in Baseline to an average of 61% following the Self-Instructional Manual. Results appeared to be due to the Self-Instructional Manual phase for 9 of the 11 participants. Following an average of 35 minutes of Feedback plus Demonstration of DTT of one task, participants’ DTT accuracy improved to an average of 91% while teaching a confederate. The improvement appeared to be due to the intervention with 10 of the 11 participants. The participants’ DTT accuracy averaged 90% during G1 and 86% during G2. These results demonstrate that this training package has considerable potential for teaching DTT to tutors, educational assistants, and parents of children with autism. / February 2008

Thesis (M. Med. Sc.)--University of Hong Kong, 2001. / Includes bibliographical references (leaves 47-55).

Thesis (Ph. D.)--University of Washington, 2003. / Vita. Includes bibliographical references (p. 158-160).

Thesis (Ph. D.)--University of Washington, 2003. / Vita. Includes bibliographical references (leaves 273-280).