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.

The cost effectiveness of Naltrexone added to cognitive-behavioral therapy in the treatment of alcohol dependence

he purpose of this study was to evaluate the comparative cost of treating alcohol dependence with either cognitive behavioral therapy (CBT) alone or CBT combined with naltrexone (CBT+naltrexone). Two hundred ninety-eight outpatients dependent on alcohol who were consecutively treated for alcohol dependence participated in this study. One hundred seven (36%) patients received adjunctive pharmacotherapy (CBT+naltrexone). The Drug Abuse Treatment Cost Analysis Program was used to estimate treatment costs. Adjunctive pharmacotherapy (CBT+naltrexone) introduced an additional treatment cost and was 54% more expensive than CBT alone. When treatment abstinence rates (36.1% CBT; 62.6% CBT+naltrexone) were applied to cost effectiveness ratios, CBT+naltrexone demonstrated an advantage over CBT alone. There were no differences between groups on a preference-based health measure (SF-6D). In this treatment center, to achieve 100 abstainers over a 12-week program, 280 patients require CBT compared with 160 CBT+naltrexone. The dominant choice was CBT+naltrexone based on modest economic advantages and significant efficiencies in the numbers needed to treat.

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

Genotyping of enterococcus faecalis and enterococcus faecium isolates using a set of eight single nucleotide polymorphisms (SNPs)

A SNP genotyping method was developed for E. faecalis and E. faecium using the 'Minimum SNPs' program. SNP sets were interrogated using allele-specific real-time PCR. SNP-typing sub-divided clonal complexes 2 and 9 of E. faecalis and 17 of E. faecium, members of which cause the majority of nosocomial infections globally.

Less food for thought : impact of attentional instructions on intrusive thoughts about snack foods

Intrusive thoughts about food may play a role in unhealthy eating behaviours. Food-related thoughts that capture attention can lead to craving and further intrusive thoughts (Kavanagh, Andrade, & May, 2005). We tested whether diverting attention to mental images or bodily sensations would reduce the incidence of intrusive thoughts about snack foods. In two experiments, participants reported their thoughts in response to probes during three 10 min periods. In the Baseline and Post-task period, participants were asked to let their mind wander. In the middle, Experimental, period, participants followed mind wandering (Control), thought diversion, or Thought Suppression instructions. Self-directed or Guided Imagery, Mindfulness-based Body Scanning, and Thought Suppression all reduced the proportion of thoughts about food, compared to Baseline. Following Body Scanning and Thought Suppression, food thoughts returned to Baseline frequencies Post-task, rather than rebounding. There were no effects of the interventions upon craving, although overall, craving and thought frequency were correlated. Thought control tasks may help people to ignore thoughts about food and thereby reduce their temptation to snack.

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

Response shift, recall bias and their effect on measuring change in health-related quality of life amongst older hospital patients

Background: Assessments of change in subjective patient reported outcomes such as health-related quality of life (HRQoL) are a key component of many clinical and research evaluations. However, conventional longitudinal evaluation of change may not agree with patient perceived change if patients' understanding of the subjective construct under evaluation changes over time (response shift) or if patients' have inaccurate recollection (recall bias). This study examined whether older adults' perception of change is in agreement with conventional longitudinal evaluation of change in their HRQoL over the duration of their hospital stay. It also investigated this level of agreement after adjusting patient perceived change for recall bias that patients may have experienced. Methods: A prospective longitudinal cohort design nested within a larger randomised controlled trial was implemented. 103 hospitalised older adults participated in this investigation at a tertiary hospital facility. The EQ-5D utility and Visual Analogue Scale (VAS) scores were used to evaluate HRQoL. Participants completed EQ-5D reports as soon as they were medically stable (within three days of admission) then again immediately prior to discharge. Three methods of change score calculation were used (conventional change, patient perceived change and patient perceived change adjusted for recall bias). Agreement was primarily investigated using intraclass correlation coefficients (ICC) and limits of agreement. Results: Overall 101 (98%) participants completed both admission and discharge assessments. The mean (SD) age was 73.3 (11.2). The median (IQR) length of stay was 38 (20-60) days. For agreement between conventional longitudinal change and patient perceived change: ICCs were 0.34 and 0.40 for EQ-5D utility and VAS respectively. For agreement between conventional longitudinal change and patient perceived change adjusted for recall bias: ICCs were 0.98 and 0.90 respectively. Discrepancy between conventional longitudinal change and patient perceived change was considered clinically meaningful for 84 (83.2%) of participants, after adjusting for recall bias this reduced to 8 (7.9%). Conclusions: Agreement between conventional change and patient perceived change was not strong. A large proportion of this disagreement could be attributed to recall bias. To overcome the invalidating effect of response shift (on conventional change) and recall bias (on patient perceived change) a method of adjusting patient perceived change for recall bias has been described.

Impaired drivers : The need to yoke treatment and sanctions

Objective: To understand the levels of substance abuse and dependence among impaired drivers by comparing the differences in patients in substance abuse treatment programs with and without a past-year DUI arrest based on their primary problem substance at admission (alcohol, cocaine, cannabis, or methamphetamine). Method: Records on 345,067 admissions to Texas treatment programs between 2005 and 2008 have been analyzed for differences in demographic characteristics, levels of severity, and mental health problems at admission, treatment completion, and 90-day follow-up. Methods will include t-tests,??, and multivariate logistic regression. Results: The analysis found that DUI arrestees with a primary problem with alcohol were less impaired than non-DUI alcohol patients, had fewer mental health problems, and were more likely to complete treatment. DUI arrestees with a primary problem with cannabis were more impaired than non-DUI cannabis patients and there was no difference in treatment completion. DUI arrestees with a primary problem with cocaine were less impaired and more likely to complete treatment than other cocaine patients, and there was little difference in levels of mental health problems. DUI arrestees with a primary problem with methamphetamine were more similar to methamphetamine non-arrestees, with no difference in mental health problems and treatment completion. Conclusions: This study provides evidence of the extent of abuse and dependence among DUI arrestees and their need for treatment for their alcohol and drug problems in order to decrease recidivism. Treatment patients with past-year DUI arrests had good treatment outcomes but closer supervision during 90 day follow-up after treatment can lead to even better long-term outcomes, including reduced recidivism. Information will be provided on the latest treatment methodologies, including medication assisted therapies and screening and brief interventions, and ways impaired driving programs and substance dependence programs can be integrated to benefit the driver and society.

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.

A polymorphism in the dysbindin gene (DTNBP1) associated with multiple psychiatric disorders including schizophrenia

Background A number of studies have found associations between dysbindin (DTNBP1) polymorphisms and schizophrenia. Recently we identified a DTNBP1 SNP (rs9370822) that is strongly associated with schizophrenia. Individuals diagnosed with schizophrenia were nearly three times as likely to carry the CC genotype compared to the AA genotype. Methods To investigate the importance of this SNP in the function of DTNBP1, a number of psychiatric conditions including addictive behaviours and anxiety disorders were analysed for association with rs9370822. Results The DTNBP1 polymorphism was significantly associated with post-traumatic stress disorder (PTSD) as well as nicotine and opiate dependence but not alcohol dependence. Individuals suffering PTSD were more than three times as likely to carry the CC genotype compared to the AA genotype. Individuals with nicotine or opiate dependence were more than twice as likely to carry the CC genotype compared to the AA genotype. Conclusions This study provides further support for the importance of DTNBP1 in psychiatric conditions and suggests that there is a common underlying molecular defect involving DTNBP1 that contributes to the development of several anxiety and addictive disorders that are generally recognised as separate clinical conditions. These disorders may actually be different expressions of a single metabolic pathway perturbation. As our participant numbers are limited our observations should be viewed with caution until they are independently replicated.