Addressing issues in sparseness, ecological bias and formulation of the adjacency matrix in Bayesian spatio-temporal analysis of disease counts

The main objective of this PhD was to further develop Bayesian spatio-temporal models (specifically the Conditional Autoregressive (CAR) class of models), for the analysis of sparse disease outcomes such as birth defects. The motivation for the thesis arose from problems encountered when analyzing a large birth defect registry in New South Wales. The specific components and related research objectives of the thesis were developed from gaps in the literature on current formulations of the CAR model, and health service planning requirements. Data from a large probabilistically-linked database from 1990 to 2004, consisting of fields from two separate registries: the Birth Defect Registry (BDR) and Midwives Data Collection (MDC) were used in the analyses in this thesis. The main objective was split into smaller goals. The first goal was to determine how the specification of the neighbourhood weight matrix will affect the smoothing properties of the CAR model, and this is the focus of chapter 6. Secondly, I hoped to evaluate the usefulness of incorporating a zero-inflated Poisson (ZIP) component as well as a shared-component model in terms of modeling a sparse outcome, and this is carried out in chapter 7. The third goal was to identify optimal sampling and sample size schemes designed to select individual level data for a hybrid ecological spatial model, and this is done in chapter 8. Finally, I wanted to put together the earlier improvements to the CAR model, and along with demographic projections, provide forecasts for birth defects at the SLA level. Chapter 9 describes how this is done. For the first objective, I examined a series of neighbourhood weight matrices, and showed how smoothing the relative risk estimates according to similarity by an important covariate (i.e. maternal age) helped improve the model’s ability to recover the underlying risk, as compared to the traditional adjacency (specifically the Queen) method of applying weights. Next, to address the sparseness and excess zeros commonly encountered in the analysis of rare outcomes such as birth defects, I compared a few models, including an extension of the usual Poisson model to encompass excess zeros in the data. This was achieved via a mixture model, which also encompassed the shared component model to improve on the estimation of sparse counts through borrowing strength across a shared component (e.g. latent risk factor/s) with the referent outcome (caesarean section was used in this example). Using the Deviance Information Criteria (DIC), I showed how the proposed model performed better than the usual models, but only when both outcomes shared a strong spatial correlation. The next objective involved identifying the optimal sampling and sample size strategy for incorporating individual-level data with areal covariates in a hybrid study design. I performed extensive simulation studies, evaluating thirteen different sampling schemes along with variations in sample size. This was done in the context of an ecological regression model that incorporated spatial correlation in the outcomes, as well as accommodating both individual and areal measures of covariates. Using the Average Mean Squared Error (AMSE), I showed how a simple random sample of 20% of the SLAs, followed by selecting all cases in the SLAs chosen, along with an equal number of controls, provided the lowest AMSE. The final objective involved combining the improved spatio-temporal CAR model with population (i.e. women) forecasts, to provide 30-year annual estimates of birth defects at the Statistical Local Area (SLA) level in New South Wales, Australia. The projections were illustrated using sixteen different SLAs, representing the various areal measures of socio-economic status and remoteness. A sensitivity analysis of the assumptions used in the projection was also undertaken. By the end of the thesis, I will show how challenges in the spatial analysis of rare diseases such as birth defects can be addressed, by specifically formulating the neighbourhood weight matrix to smooth according to a key covariate (i.e. maternal age), incorporating a ZIP component to model excess zeros in outcomes and borrowing strength from a referent outcome (i.e. caesarean counts). An efficient strategy to sample individual-level data and sample size considerations for rare disease will also be presented. Finally, projections in birth defect categories at the SLA level will be made.

Bias in the nonlinear filter generator output sequence

Nonlinear filter generators are common components used in the keystream generators for stream ciphers and more recently for authentication mechanisms. They consist of a Linear Feedback Shift Register (LFSR) and a nonlinear Boolean function to mask the linearity of the LFSR output. Properties of the output of a nonlinear filter are not well studied. Anderson noted that the m-tuple output of a nonlinear filter with consecutive taps to the filter function is unevenly distributed. Current designs use taps which are not consecutive. We examine m-tuple outputs from nonlinear filter generators constructed using various LFSRs and Boolean functions for both consecutive and uneven (full positive difference sets where possible) tap positions. The investigation reveals that in both cases, the m-tuple output is not uniform. However, consecutive tap positions result in a more biased distribution than uneven tap positions, with some m-tuples not occurring at all. These biased distributions indicate a potential flaw that could be exploited for cryptanalysis.

Bias in the nonlinear filter generator output sequence

Nonlinear filter generators are common components used in the keystream generators for stream ciphers and more recently for authentication mechanisms. They consist of a Linear Feedback Shift Register (LFSR) and a nonlinear Boolean function to mask the linearity of the LFSR output. Properties of the output of a nonlinear filter are not well studied. Anderson noted that the m-tuple output of a nonlinear filter with consecutive taps to the filter function is unevenly distributed. Current designs use taps which are not consecutive. We examine m-tuple outputs from nonlinear filter generators constructed using various LFSRs and Boolean functions for both consecutive and uneven (full positive difference sets where possible) tap positions. The investigation reveals that in both cases, the m-tuple output is not uniform. However, consecutive tap positions result in a more biased distribution than uneven tap positions, with some m-tuples not occurring at all. These biased distributions indicate a potential flaw that could be exploited for cryptanalysis

Reference bias : presentation of extreme health states prior to EQ-VAS improves health-related quality of life scores. A randomised crossover trial.

Background: Clinical practice and clinical research has made a concerted effort to move beyond the use of clinical indicators alone and embrace patient focused care through the use of patient reported outcomes such as healthrelated quality of life. However, unless patients give consistent consideration to the health states that give meaning to measurement scales used to evaluate these constructs, longitudinal comparison of these measures may be invalid. This study aimed to investigate whether patients give consideration to a standard health state rating scale (EQ-VAS) and whether consideration of good and poor health state descriptors immediately changes their selfreport. Methods: A randomised crossover trial was implemented amongst hospitalised older adults (n = 151). Patients were asked to consider descriptions of extremely good (Description-A) and poor (Description-B) health states. The EQ-VAS was administered as a self-report at baseline, after the first descriptors (A or B), then again after the remaining descriptors (B or A respectively). At baseline patients were also asked if they had considered either EQVAS anchors. Results: Overall 106/151 (70%) participants changed their self-evaluation by ≥5 points on the 100 point VAS, with a mean (SD) change of +4.5 (12) points (p < 0.001). A total of 74/151 (49%) participants did not consider the best health VAS anchor, of the 77 who did 59 (77%) thought the good health descriptors were more extreme (better) then they had previously considered. Similarly 85/151 (66%) participants did not consider the worst health anchor of the 66 who did 63 (95%) thought the poor health descriptors were more extreme (worse) then they had previously considered. Conclusions: Health state self-reports may not be well considered. An immediate significant shift in response can be elicited by exposure to a mere description of an extreme health state despite no actual change in underlying health state occurring. Caution should be exercised in research and clinical settings when interpreting subjective patient reported outcomes that are dependent on brief anchors for meaning. Trial Registration: Australian and New Zealand Clinical Trials Registry (#ACTRN12607000606482) http://www.anzctr. org.au

Young drivers’ optimism bias for accident risk and driving skill : accountability and insight experience manipulations

This study aimed to determine whether two brief, low cost interventions would reduce young drivers’ optimism bias for their driving skills and accident risk perceptions. This tendency for such drivers to perceive themselves as more skilful and less prone to driving accidents than their peers may lead to less engagement in precautionary driving behaviours and a greater engagement in more dangerous driving behaviour. 243 young drivers (aged 17 - 25 years) were randomly allocated to one of three groups: accountability, insight or control. All participants provided both overall and specific situation ratings of their driving skills and accident risk relative to a typical young driver. Prior to completing the questionnaire, those in the accountability condition were first advised that their driving skills and accident risk would be later assessed via a driving simulator. Those in the insight condition first underwent a difficult computer-based hazard perception task designed to provide participants with insight into their potential limitations when responding to hazards in difficult and unpredictable driving situations. Participants in the control condition completed only the questionnaire. Results showed that the accountability manipulation was effective in reducing optimism bias in terms of participants’ comparative ratings of their accident risk in specific situations, though only for less experienced drivers. In contrast, among more experienced males, participants in the insight condition showed greater optimism bias for overall accident risk than their counterparts in the accountability or control groups. There were no effects of the manipulations on drivers’ skills ratings. The differential effects of the two types of manipulations on optimism bias relating to one’s accident risk in different subgroups of the young driver sample highlight the importance of targeting interventions for different levels of experience. Accountability interventions may be beneficial for less experienced young drivers but the results suggest exercising caution with the use of insight type interventions, particularly hazard perception style tasks, for more experienced young drivers typically still in the provisional stage of graduated licensing systems.

Data and process requirements for product recall coordination

When an organisation becomes aware that one of its products may pose a safety risk to customers, it must take appropriate action as soon as possible or it can be held liable. The ability to automatically trace potentially dangerous goods through the supply chain would thus help organisations fulfill their legal obligations in a timely and effective manner. Furthermore, product recall legislation requires manufacturers to separately notify various government agencies, the health department and the public about recall incidents. This duplication of effort and paperwork can introduce errors and data inconsistencies. In this paper, we examine traceability and notification requirements in the product recall domain from two perspectives: the activities carried out during the manufacturing and recall processes and the data collected during the enactment of these processes. We then propose a workflow-based coordination framework to support these data and process requirements.

PCR bias Toward the wild-type k-ras and p53 sequences: Implications for PCR detection of mutations and cancer diagnosis

PCR-based cancer diagnosis requires detection of rare mutations in k- ras, p53 or other genes. The assumption has been that mutant and wild-type sequences amplify with near equal efficiency, so that they are eventually present in proportions representative of the starting material. Work on factor IX suggests that this assumption is invalid for one case of near- sequence identity. To test the generality of this phenomenon and its relevance to cancer diagnosis, primers distant from point mutations in p53 and k-ras were used to amplify wild-type and mutant sequences from these genes. A substantial bias against PCR amplification of mutants was observed for two regions of the p53 gene and one region of k-ras. For k-ras and p53, bias was observed when the wild-type and mutant sequences were amplified separately or when mixed in equal proportions before PCR. Bias was present with proofreading and non-proofreading polymerase. Mutant and wild-type segments of the factor V, cystic fibrosis transmembrane conductance regulator and prothrombin genes were amplified and did not exhibit PCR bias. Therefore, the assumption of equal PCR efficiency for point mutant and wild-type sequences is invalid in several systems. Quantitative or diagnostic PCR will require validation for each locus, and enrichment strategies may be needed to optimize detection of mutants.

Reversed bias Pt/nanostructured ZnO Schottky diode with enhanced electric field for hydrogen sensing

In this paper, the effect of electric field enhancement on Pt/nanostructured ZnO Schottky diode based hydrogen sensors under reverse bias condition has been investigated. Current-voltage characteristics of these diodes have been studied at temperatures from 25 to 620 °C and their free carrier density concentration was estimated by exposing the sensors to hydrogen gas. The experimental results show a significantly lower breakdown voltage in reversed bias current-voltage characteristics than the conventional Schottky diodes and also greater lateral voltage shift in reverse bias operation than the forward bias. This can be ascribed to the increased localized electric fields emanating from the sharp edges and corners of the nanostructured morphologies. At 620 °C, voltage shifts of 114 and 325 mV for 0.06% and 1% hydrogen have been recorded from dynamic response under the reverse bias condition. © 2010 Elsevier B.V. All rights reserved.