With societies aging all around the world, the global burden of degenerative diseases is expected to increase exponentially. From the perspective drug development, degenerative diseases represent an especially challenging class. Clinical trials, in this context often termed disease progression studies, are long, costly, require many individuals, and have low success rates. Therefore, it is crucial to use informative study designs and to analyze efficiently the obtained trial data. The development of novel approaches intended towards facilitating both the design and the analysis of disease progression studies was the aim of this thesis. This aim was pursued in three stages (i) the characterization and extension of pharmacometric software, (ii) the development of new methodology around statistical power, and (iii) the demonstration of application benefits. The optimal design software PopED was extended to simplify the application of optimal design methodology when planning a disease progression study. The performance of non-linear mixed effect estimation algorithms for trial data analysis was evaluated in terms of bias, precision, robustness with respect to initial estimates, and runtime. A novel statistic allowing for explicit optimization of study design for statistical power was derived and found to perform superior to existing methods. Monte-Carlo power studies were accelerated through application of parametric power estimation, delivering full power versus sample size curves from a few hundred Monte-Carlo samples. Optimal design and an explicit optimization for statistical power were applied to the planning of a study in Alzheimer's disease, resulting in a 30% smaller study size when targeting 80% power. The analysis of ADAS-cog score data was improved through application of item response theory, yielding a more exact description of the assessment score, an increased statistical power and an enhanced insight in the assessment properties. In conclusion, this thesis presents novel pharmacometric methods that can help addressing the challenges of designing and planning disease progression studies.

国立情報学研究所で電子化したコンテンツを使用している。

国立情報学研究所で電子化したコンテンツを使用している。

国立情報学研究所で電子化したコンテンツを使用している。

国立情報学研究所で電子化したコンテンツを使用している。

国立情報学研究所で電子化したコンテンツを使用している。

国立情報学研究所で電子化したコンテンツを使用している。

国立情報学研究所で電子化したコンテンツを使用している。

Doctor of Philosophy (PhD) / In the last two decades, ambivalence has emerged as one of the primary concerns of attitude researchers. The acknowledgement that individuals can simultaneously evaluate an attitude object as both positive and negative has challenged a number of the status quos of the attitude literature. This thesis utilises an unfolding approach to investigate the implications of ambivalence for the conceptualisation of attitudes and their measurement. Firstly, the assumption that ambivalence is at odds with the bipolar understanding of attitudes was investigated. The results suggested that ambivalence is consistent with bipolarity, whereby ambivalent attitudes are located at the centre of the bipolar dimension. Secondly, attitude scales for the abortion, euthanasia and Aboriginal Australians issues were constructed to reflect this bipolar understanding. The fit of these statements to Coombs’ (1964) unidimensional unfolding theory provided evidence that ambivalence is also consistent with the quantitative conceptualisation of attitudes. Together these results provided further validation of the unfolding approach to attitude measurement. These models alleviate many of the problems faced by the ubiquitous method of summated ratings, including the assessment of ambivalent evaluations. Finally, these scales were used to investigate the latent structure of attitudes and its relationship with meta-psychological judgements of ambivalence. The conclusions drawn from these analyses were limited by a number of issues, highlighting the importance of rigorously considering measurement issues for all attitude parameters. Nonetheless, they presented preliminary validation of these scales’ ability to measure ambivalent evaluations and suggested a systematic relationship between proximity to the centre of the evaluative dimension and metapsychological ambivalence. Overall, it is concluded that a number of assumptions regarding the implications of ambivalence are misplaced and the proposed solutions are even more troublesome. Suggestions for future research are made, particularly with respect to differentiating between ambivalent, indifferent and uncertain evaluative states. Furthermore, attitude researchers are encouraged to discard their operationalist biases in order to engage with the measurement issues illuminated throughout this thesis. This is necessary to account for the complexity of the attitude construct, which ambivalence is testament to.

Doctor of Philosophy (PhD) / In the last two decades, ambivalence has emerged as one of the primary concerns of attitude researchers. The acknowledgement that individuals can simultaneously evaluate an attitude object as both positive and negative has challenged a number of the status quos of the attitude literature. This thesis utilises an unfolding approach to investigate the implications of ambivalence for the conceptualisation of attitudes and their measurement. Firstly, the assumption that ambivalence is at odds with the bipolar understanding of attitudes was investigated. The results suggested that ambivalence is consistent with bipolarity, whereby ambivalent attitudes are located at the centre of the bipolar dimension. Secondly, attitude scales for the abortion, euthanasia and Aboriginal Australians issues were constructed to reflect this bipolar understanding. The fit of these statements to Coombs’ (1964) unidimensional unfolding theory provided evidence that ambivalence is also consistent with the quantitative conceptualisation of attitudes. Together these results provided further validation of the unfolding approach to attitude measurement. These models alleviate many of the problems faced by the ubiquitous method of summated ratings, including the assessment of ambivalent evaluations. Finally, these scales were used to investigate the latent structure of attitudes and its relationship with meta-psychological judgements of ambivalence. The conclusions drawn from these analyses were limited by a number of issues, highlighting the importance of rigorously considering measurement issues for all attitude parameters. Nonetheless, they presented preliminary validation of these scales’ ability to measure ambivalent evaluations and suggested a systematic relationship between proximity to the centre of the evaluative dimension and metapsychological ambivalence. Overall, it is concluded that a number of assumptions regarding the implications of ambivalence are misplaced and the proposed solutions are even more troublesome. Suggestions for future research are made, particularly with respect to differentiating between ambivalent, indifferent and uncertain evaluative states. Furthermore, attitude researchers are encouraged to discard their operationalist biases in order to engage with the measurement issues illuminated throughout this thesis. This is necessary to account for the complexity of the attitude construct, which ambivalence is testament to.