Bayesian indirect inference using a parametric auxiliary model

Indirect inference (II) is a methodology for estimating the parameters of an intractable (generative) model on the basis of an alternative parametric (auxiliary) model that is both analytically and computationally easier to deal with. Such an approach has been well explored in the classical literature but has received substantially less attention in the Bayesian paradigm. The purpose of this paper is to compare and contrast a collection of what we call parametric Bayesian indirect inference (pBII) methods. One class of pBII methods uses approximate Bayesian computation (referred to here as ABC II) where the summary statistic is formed on the basis of the auxiliary model, using ideas from II. Another approach proposed in the literature, referred to here as parametric Bayesian indirect likelihood (pBIL), we show to be a fundamentally different approach to ABC II. We devise new theoretical results for pBIL to give extra insights into its behaviour and also its differences with ABC II. Furthermore, we examine in more detail the assumptions required to use each pBII method. The results, insights and comparisons developed in this paper are illustrated on simple examples and two other substantive applications. The first of the substantive examples involves performing inference for complex quantile distributions based on simulated data while the second is for estimating the parameters of a trivariate stochastic process describing the evolution of macroparasites within a host based on real data. We create a novel framework called Bayesian indirect likelihood (BIL) which encompasses pBII as well as general ABC methods so that the connections between the methods can be established.

Interactions between cars and motorcycles testing underlying concepts through integration of on-road and simulator studies

We conducted on-road and simulator studies to explore the mechanisms underpinning driver-rider crashes. In Study 1 the verbal protocols of 40 drivers and riders were assessed at intersections as part of a 15km on-road route in Melbourne. Network analysis of the verbal transcripts highlighted key differences in the situation awareness of drivers and riders at intersections. In a further study using a driving simulator we examined in car drivers the influence of acute exposure to motorcyclists. In a 15 min simulated drive, 40 drivers saw either no motorcycles or a high number of motorcycles in the surrounding traffic. In a subsequent 45-60 min drive, drivers were asked to detect motorcycles in traffic. The proportion of motorcycles was manipulated so that there was either a high (120) or low (6) number of motorcycles during the drive. Those drivers exposed to a high number of motorcycles were significantly faster at detecting motorcycles. Fundamentally, the incompatible situation awareness at intersections by drivers and riders underpins the conflicts. Study 2 offers some suggestion for a countermeasure here, although more research around schema and exposure training to support safer interactions is needed.

Sleepiness : how a biological drive can influence other risky road user behaviours

The Safe System approach to road safety utilises a holistic view of the interactions among vehicles, roads and road users. Yet, the contribution of each of these factors to crashes is vastly different. The role of road users is widely acknowledged as an overwhelming contributor to road crashes. Substantial gains have been made with improvements to vehicle and roads over a number of years. However, improvements of the road user’s behaviour has been (in some cases) less substantial. A road user behaviour that is relatively unregulated is driver sleepiness, which is part of the ‘fatal five’ of risky road user behaviours. The effect of sleepiness is ubiquitous – sleepiness is a state that most, if not all drivers on our roads has experienced, and is habitually exposed to. The quality and quantity of daily sleep is integral to our level of neurobehavioural performance during wakefulness and as such can have a compounding effect on a number of other risky driving behaviours. This paper will discuss the potential influence of sleepiness as an interceding factor for a number of risky driving behaviours. Little effort has been given to increasing awareness of the deleterious and wide ranging effects that sleepiness has on road safety. Given the wide ranging influence of sleepiness, improvements of ‘sleep health’ as a protective factor at the community or individual level could lead to significant reductions in road trauma and increases of general well being. A discussion of potential actions to reduce sleepiness is required if reductions of road trauma are to continue.

A high-throughput panel for identifying clinically relevant mutation profiles in melanoma

Success with molecular-based targeted drugs in the treatment of cancer has ignited extensive research efforts within the field of personalized therapeutics. However, successful application of such therapies is dependent on the presence or absence of mutations within the patient's tumor that can confer clinical efficacy or drug resistance. Building on these findings, we developed a high-throughput mutation panel for the identification of frequently occurring and clinically relevant mutations in melanoma. An extensive literature search and interrogation of the Catalogue of Somatic Mutations in Cancer database identified more than 1,000 melanoma mutations. Applying a filtering strategy to focus on mutations amenable to the development of targeted drugs, we initially screened 120 known mutations in 271 samples using the Sequenom MassARRAY system. A total of 252 mutations were detected in 17 genes, the highest frequency occurred in BRAF (n = 154, 57%), NRAS (n = 55, 20%), CDK4 (n = 8, 3%), PTK2B (n = 7, 2.5%), and ERBB4 (n = 5, 2%). Based on this initial discovery screen, a total of 46 assays interrogating 39 mutations in 20 genes were designed to develop a melanoma-specific panel. These assays were distributed in multiplexes over 8 wells using strict assay design parameters optimized for sensitive mutation detection. The final melanoma-specific mutation panel is a cost effective, sensitive, high-throughput approach for identifying mutations of clinical relevance to molecular-based therapeutics for the treatment of melanoma. When used in a clinical research setting, the panel may rapidly and accurately identify potentially effective treatment strategies using novel or existing molecularly targeted drugs

Identification of TFG (TRK-fused gene) as a putative metastatic melanoma tumor suppressor gene

High density SNP arrays can be used to identify DNA copy number changes in tumors such as homozygous deletions of tumor suppressor genes and focal amplifications of oncogenes. Illumina Human CNV370 Bead chip arrays were used to assess the genome for unbalanced chromosomal events occurring in 39 cell lines derived from stage III metastatic melanomas. A number of genes previously recognized to have an important role in the development and progression of melanoma were identified including homozygous deletions of CDKN2A (13 of 39 samples), CDKN2B (10 of 39), PTEN (3 of 39), PTPRD (3 of 39), TP53 (1 of 39), and amplifications of CCND1 (2 of 39), MITF (2 of 39), MDM2 (1 of 39), and NRAS (1 of 39). In addition, a number of focal homozygous deletions potentially targeting novel melanoma tumor suppressor genes were identified. Because of their likely functional significance for melanoma progression, FAS, CH25H, BMPR1A, ACTA2, and TFG were investigated in a larger cohort of melanomas through sequencing. Nonsynonymous mutations were identified in BMPR1A (1 of 43), ACTA2 (3 of 43), and TFG (5 of 103). A number of potentially important mutation events occurred in TFG including the identification of a mini mutation ‘‘hotspot’’ at amino acid residue 380 (P380S and P380L) and the presence of multiple mutations in two melanomas. Mutations in TFG may have important clinical relevance for current therapeutic strategies to treat metastatic melanoma.

Efficacy of proxy definitions for identification of fatigue/sleep-related crashes : an Australian evaluation

Fatigue/sleepiness is recognised as an important contributory factor in fatal and serious injury road traffic incidents (RTIs), however, identifying fatigue/sleepiness as a causal factor remains an uncertain science. Within Australia attending police officers at a RTI report the causal factors; one option is fatigue/sleepiness. In some Australian jurisdictions police incident databases are subject to post hoc analysis using a proxy definition for fatigue/sleepiness. This secondary analysis identifies further RTIs caused by fatigue/sleepiness not initially identified by attending officers. The current study investigates the efficacy of such proxy definitions for attributing fatigue/sleepiness as a RTI causal factor. Over 1600 Australian drivers were surveyed regarding their experience and involvement in fatigue/sleep-related RTIs and near-misses during the past five years. Driving while fatigued/sleepy had been experienced by the majority of participants (66.0% of participants). Fatigue/sleep-related near misses were reported by 19.1% of participants, with 2.4% being involved in a fatigue/sleep-related RTI. Examination of the characteristics for the most recent event (either a near miss or crash) found that the largest proportion of incidents (28.0%) occurred when commuting to or from work, followed by social activities (25.1%), holiday travel (19.8%), or for work purposes (10.1%). The fatigue/sleep related RTI and near-miss experience of a representative sample of Australian drivers does not reflect the proxy definitions used for fatigue/sleepiness identification. In particular those RTIs that occur in urban areas and at slow speeds may not be identified. While important to have a strategy for identifying fatigue/sleepiness related RTIs proxy measures appear best suited to identifying specific subsets of such RTIs.

Fully Bayesian experimental design for pharmacokinetic studies

Utility functions in Bayesian experimental design are usually based on the posterior distribution. When the posterior is found by simulation, it must be sampled from for each future data set drawn from the prior predictive distribution. Many thousands of posterior distributions are often required. A popular technique in the Bayesian experimental design literature to rapidly obtain samples from the posterior is importance sampling, using the prior as the importance distribution. However, importance sampling will tend to break down if there is a reasonable number of experimental observations and/or the model parameter is high dimensional. In this paper we explore the use of Laplace approximations in the design setting to overcome this drawback. Furthermore, we consider using the Laplace approximation to form the importance distribution to obtain a more efficient importance distribution than the prior. The methodology is motivated by a pharmacokinetic study which investigates the effect of extracorporeal membrane oxygenation on the pharmacokinetics of antibiotics in sheep. The design problem is to find 10 near optimal plasma sampling times which produce precise estimates of pharmacokinetic model parameters/measures of interest. We consider several different utility functions of interest in these studies, which involve the posterior distribution of parameter functions.

Commencing nursing students' perceptions and anxiety of bioscience

It is known that bioscience is perceived to be difficult and causes anxiety within undergraduate nursing students; yet, commencing students' perceptions of bioscience is not known. Therefore, the aim of this study was to ascertain incoming students' perceptions, knowledge and approaches to learning bioscience. Incoming students to the Bachelor of Nursing completed a questionnaire prior to undertaking bioscience. Two hundred and seventy three students completed the questionnaire that explored their expectations, preconceptions of bioscience content, approaches to learning bioscience, and relationship to clinical practice in the context of biosciences. Participant ages ranged from 17 to 53 (mean 23 years), and 78% of students had completed at least one secondary school science subject, of which 60% had studied biology. Overall, students' preconceptions included anxiety about studying bioscience, bioscience being difficult and harder than nursing subjects, and that more content will be required for bioscience than nursing subjects. Analysis using ANOVA revealed the relationships for secondary school science and age on student responses. A significant effect of secondary school science was found for science in school being advantageous for bioscience (p = 0.010), understanding what bioscience entails (p = 0.002), needing to study science prior to the start of the semester (p = 0.009), and that bioscience is considered difficult (p = 0.029). A significant effect of age was found for exams being more difficult than other assessments (p = 0.000) and for being able to see the relevance of nursing when reaching the workplace (p = 0.011). The findings also indicated that perceptions and associated anxieties related to bioscience were present in commencing students, similar to those which have been reported previously in established student groups. This strongly suggests that the faculty should attempt to dispel preconceptions about bioscience and target improved supports to facilitate the transition of students into the commencement of bioscience for nursing students.

Designing a seasonality application to support urban agriculture practice

This position paper describes the work in progress towards the goal of building a technical prototype that enables users – those who have little or no knowledge and experience engaging in urban agriculture – to receive information personalised to their location and situation, and allow them to ask questions and share experiences with others. We describe the design process thus far, informed by a survey and a workshop with experts in the field, before concluding with the future direction of this work.

Molecular biomarkers in non-small-cell lung cancer : a retrospective analysis of data from the phase 3 FLEX study

Background: Findings from the phase 3 FLEX study showed that the addition of cetuximab to cisplatin and vinorelbine significantly improved overall survival, compared with cisplatin and vinorelbine alone, in the first-line treatment of EGFR-expressing, advanced non-small-cell lung cancer (NSCLC). We investigated whether candidate biomarkers were predictive for the efficacy of chemotherapy plus cetuximab in this setting. Methods: Genomic DNA extracted from formalin-fixed paraffin-embedded (FFPE) tumour tissue of patients enrolled in the FLEX study was screened for KRAS codon 12 and 13 and EGFR kinase domain mutations with PCR-based assays. In FFPE tissue sections, EGFR copy number was assessed by dual-colour fluorescence in-situ hybridisation and PTEN expression by immunohistochemistry. Treatment outcome was investigated according to biomarker status in all available samples from patients in the intention-to-treat population. The primary endpoint in the FLEX study was overall survival. The FLEX study, which is ongoing but not recruiting participants, is registered with ClinicalTrials.gov, number NCT00148798. Findings: KRAS mutations were detected in 75 of 395 (19%) tumours and activating EGFR mutations in 64 of 436 (15%). EGFR copy number was scored as increased in 102 of 279 (37%) tumours and PTEN expression as negative in 107 of 303 (35%). Comparisons of treatment outcome between the two groups (chemotherapy plus cetuximab vs chemotherapy alone) according to biomarker status provided no indication that these biomarkers were of predictive value. Activating EGFR mutations were identified as indicators of good prognosis, with patients in both treatment groups whose tumours carried such mutations having improved survival compared with those whose tumours did not (chemotherapy plus cetuximab: median 17·5 months [95% CI 11·7-23·4] vs 8·5 months [7·1-10·8], hazard ratio [HR] 0·52 [0·32-0·84], p=0·0063; chemotherapy alone: 23·8 months [15·2-not reached] vs 10·0 months [8·7-11·0], HR 0·35 [0·21-0·59], p<0·0001). Expression of PTEN seemed to be a potential indicator of good prognosis, with patients whose tumours expressed PTEN having improved survival compared with those whose tumours did not, although this finding was not significant (chemotherapy plus cetuximab: median 11·4 months [8·6-13·6] vs 6·8 months [5·9-12·7], HR 0·80 [0·55-1·16], p=0·24; chemotherapy alone: 11·0 months [9·2-12·6] vs 9·3 months [7·6-11·9], HR 0·77 [0·54-1·10], p=0·16). Interpretation: The efficacy of chemotherapy plus cetuximab in the first-line treatment of advanced NSCLC seems to be independent of each of the biomarkers assessed. Funding: Merck KGaA. © 2011 Elsevier Ltd.

Psychotropic medication use in adolescents with intellectual disability living in the community

Purpose Information on the use of psychotropic medications in adolescents with intellectual disability is scant. Such information can guide interventions to improve psychotropic medication use in this population. We investigated the prevalence of, and factors associated with, psychotropic medication use in adolescents with intellectual disability in Australia who live in the community. Methods Cross-sectional data were obtained from adolescents with intellectual disability living in the community in South East Queensland, Australia, between February 2007 and September 2010. Self-reported information on medication use was extracted from a health screening tool. Demographic and medical data were collected through parent/caregiver surveys. Medications were classified according to the Anatomical Therapeutic Chemical classification system. Psychopathology was assessed using the Developmental Behaviour Checklist Short Form. Logistic regression analysis was used to assess the association of demographic and medical characteristics with psychotropic medication use. Results There were 176 participants (median age = 16 years, range = 11–19 years; 55% male). Psychotropics were used by 20% of participants. Psychostimulants were the commonest psychotropic class, used by 9% of participants. Multipsychotropic prescribing was not common with only seven participants using more than one psychotropic agent. After adjusting for potentially confounding variables, use of psychotropic medications was significantly associated with male gender (adjusted odds ratio = 3.6; 95% confidence interval = 1.3–9.5) and having major behaviour problems (3.1; 1.1–8.9). Conclusions Adolescents with intellectual disability use a wide range of psychotropic medications. Being male and having major behaviour problems are associated with the use of psychotropic medications. Research examining the rationale for psychotropic prescribing in this population is needed. Copyright © 2013 John Wiley & Sons, Ltd.

Bioavailability study of oral and intravenous OGT 719, a novel nucleoside analogue with preferential activity in the liver

Purpose: Although oral fluoropyrimidine pro-drugs are increasingly being administered in preference to intravenous nucleoside analogues in cancer chemotherapy, their activation in malignant liver tissue may be insufficient. OGT 719 (1-galactopyranosyl-5-fluorouracil) is a novel nucleoside analogue, preferentially localized in hepatocytes and hepatoma cells via the asialoglycoprotein receptor. The aim of this study was to assess the systemic bioavailability of this rationally designed drug in 16 patients with advanced solid cancers. Method: Crossover pharmacokinetic study of oral (400 or 800 mg) and intravenous (250 mg/m 2) OGT 719. Results: Linear pharmacokinetics and oral bioavailability of approximately 25% were observed at the dose levels used in this study. Like other 5-FU prodrugs, considerable interpatient variability was observed in bioavailability following oral dosing. The mean half-life for oral doses was 4 h. OGT 719 was well tolerated. No objective tumour responses were demonstrated. Conclusion: The systemic bioavailability and half-life of oral OGT 719 are sufficient to merit dose escalation studies with frequent daily dosing. Subsequent efficacy studies should be performed in patients with primary and secondary liver malignancies.

Bioavailability study of oral and intravenous OGT 719, a novel nucleoside analogue with preferential activity in the liver

Purpose: Although oral fluoropyrimidine pro-drugs are increasingly being administered in preference to intravenous nucleoside analogues in cancer chemotherapy, their activation in malignant liver tissue may be insufficient. OGT 719 (1-galactopyranosyl-5-fluorouracil) is a novel nucleoside analogue, preferentially localized in hepatocytes and hepatoma cells via the asialoglycoprotein receptor. The aim of this study was to assess the systemic bioavailability of this rationally designed drug in 16 patients with advanced solid cancers. Method: Crossover pharmacokinetic study of oral (400 or 800 mg) and intravenous (250 mg/m 2) OGT 719. Results: Linear pharmacokinetics and oral bioavailability of approximately 25% were observed at the dose levels used in this study. Like other 5-FU prodrugs, considerable interpatient variability was observed in bioavailability following oral dosing. The mean half-life for oral doses was 4 h. OGT 719 was well tolerated. No objective tumour responses were demonstrated. Conclusion: The systemic bioavailability and half-life of oral OGT 719 are sufficient to merit dose escalation studies with frequent daily dosing. Subsequent efficacy studies should be performed in patients with primary and secondary liver malignancies.

Expression of thrombospondin-1 in resected colorectal liver metastases predicts poor prognosis

Purpose The aim of this study was to examine the expression and prognostic relevance of thrombospondin-1 (TSP-1) in tumor biopsies taken from a consecutive series of liver resections done at the University Hospitals of Leicester and the Royal Liverpool Hospital. Experimental Design Patients having undergone a liver resection for colorectal liver metastases at our institutions between 1993 and 1999 inclusive were eligible. Inclusion criteria were curative intent, sufficient tumor biopsy, and patient follow-up data. One hundred eighty-two patients were considered in this study. Standard immunohistochemical techniques were used to study the expression of TSP-1 in 5-μm tumor sections from paraffin-embedded tissue blocks. TSP-1 was correlated with survival using the Kaplan-Meier method and log-rank test for univariate analysis and the Cox proportional hazard model for multivariate analysis. Results One hundred eighty-two patients (male, n = 122 and female, n = 60) ages between 25 and 81 years (mean, 61 years) were included. TSP-1 was expressed around blood vessels (n = 45, 25%) or in the stroma (n = 59, 33%). No expression was detected in the remaining tumors. TSP-1 significantly correlated with poor survival on univariate (P = 0.01 for perivascular expression and P = 0.03 for stromal expression) and multivariate analysis (P = 0.01 for perivascular expression). Conclusion TSP-1 is a negatively prognostic factor for survival in resected colorectal liver metastases. © 2005 American Association for Cancer Research.

Cloning and characterization of microRNAs from Brassica napus

A library containing approximately 40,000 small RNA sequences was constructed for Brassica napus. Analysis of 3025 sequences obtained from this library resulted in the identification of 11 conserved miRNA families, which were validated by secondary structure prediction using surrounding sequences in the Brassica genome. Two 21 nt small RNA sequences reside within the arm of a pre-miRNA like stem-loop structure, making them likely candidates for novel non-conserved miRNAs in B. napus. Most of the conserved miRNAs were expressed at similar levels in a F1 hybrid B. napus line and its four double haploid progeny that showed marked variations in phenotypes, but many were differentially expressed between B. napus and Arabidopsis. The miR169 family was expressed at high levels in young leaves and stems, but was undetectable in roots and mature leaves, suggesting that miR169 expression is developmentally regulated in B. napus. © 2007 Federation of European Biochemical Societies.