Statistical models for cancer screening

This paper reviews the application of statistical models to planning and evaluating cancer screening programmes. Models used to analyse screening strategies can be classified as either surface models, which consider only those events which can be directly observed such as disease incidence, prevalence or mortality, or deep models, which incorporate hypotheses about the disease process that generates the observed events. This paper focuses on the latter type. These can be further classified as analytic models, which use a model of the disease to derive direct estimates of characteristics of the screening procedure and its consequent benefits, and simulation models, which use the disease model to simulate the course of the disease in a hypothetical population with and without screening and derive measures of the benefit of screening from the simulation outcomes. The main approaches to each type of model are described and an overview given of their historical development and strengths and weaknesses. A brief review of fitting and validating such models is given and finally a discussion of the current state of, and likely future trends in, cancer screening models is presented.

The population cost-effectiveness of delivering universal and indicated school-based interventions to prevent the onset of major depression among youth in Australia

AIMS: School-based psychological interventions encompass: universal interventions targeting youth in the general population; and indicated interventions targeting youth with subthreshold depression. This study aimed to: (1) examine the population cost-effectiveness of delivering universal and indicated prevention interventions to youth in the population aged 11-17 years via primary and secondary schools in Australia; and (2) compare the comparative cost-effectiveness of delivering these interventions using face-to-face and internet-based delivery mechanisms. METHODS: We reviewed literature on the prevention of depression to identify all interventions targeting youth that would be suitable for implementation in Australia and had evidence of efficacy to support analysis. From this, we found evidence of effectiveness for the following intervention types: universal prevention involving group-based psychological interventions delivered to all participating school students; and indicated prevention involving group-based psychological interventions delivered to students with subthreshold depression. We constructed a Markov model to assess the cost-effectiveness of delivering universal and indicated interventions in the population relative to a 'no intervention' comparator over a 10-year time horizon. A disease model was used to simulate epidemiological transitions between three health states (i.e., healthy, diseased and dead). Intervention effect sizes were based on meta-analyses of randomised control trial data identified in the aforementioned review; while health benefits were measured as Disability-adjusted Life Years (DALYs) averted attributable to reductions in depression incidence. Net costs of delivering interventions were calculated using relevant Australian data. Uncertainty and sensitivity analyses were conducted to test model assumptions. Incremental cost-effectiveness ratios (ICERs) were measured in 2013 Australian dollars per DALY averted; with costs and benefits discounted at 3%. RESULTS: Universal and indicated psychological interventions delivered through face-to-face modalities had ICERs below a threshold of $50 000 per DALY averted. That is, $7350 per DALY averted (95% uncertainty interval (UI): dominates - 23 070) for universal prevention, and $19 550 per DALY averted (95% UI: 3081-56 713) for indicated prevention. Baseline ICERs were generally robust to changes in model assumptions. We conducted a sensitivity analysis which found that internet-delivered prevention interventions were highly cost-effective when assuming intervention effect sizes of 100 and 50% relative to effect sizes observed for face-to-face delivered interventions. These results should, however, be interpreted with caution due to the paucity of data. CONCLUSIONS: School-based psychological interventions appear to be cost-effective. However, realising efficiency gains in the population is ultimately dependent on ensuring successful system-level implementation.

The zebrafish as a model system for human disease

The zebrafish (Danio rerio) has been widely utilised for the study of developmental biology, which has lead to the evolution of sophisticated cellular and molecular approaches. More recently, the rapid progress of various zebrafish genomic infrastructure initiatives is facilitating the development of zebrafish models of human disease. This review aims to describe several representative examples of how the zebrafish can be successfully used to identify novel genes and assign gene function, providing invaluable clues to human pathophysiology.

Correction of a mouse model of Menkes disease by the human Menkes gene

The brindled mouse is an accurate model of the fatal human X-linked copper deficiency disorder, Menkes disease. Males carrying the mutant allele of the Menkes gene orthologue Atp7a die in the second week of life. To determine whether the genetic defect in the brindled mice could be corrected by expression of the human Menkes gene, male transgenic mice expressing ATP7A from the chicken β-actin composite promoter (CAG) were mated with female carriers of the brindled mutation (Atp7aMo-br). Mutant males carrying the transgene survived and were fertile but the copper defect was not completely corrected. Unexpectedly males corrected with one transgenic line (T25#5) were mottled and resembled carrier females, this effect appeared to be caused by mosaic expression of the transgene. In contrast, males corrected with another line (T22#2) had agouti coats. Copper concentrations in tissues of the rescued mutants also resembled those of the heterozygous females, with high levels in kidney (84.6 ± 4.9 μg/g in corrected males vs. 137.0 ± 44.3 μg/g in heterozygotes) and small intestine (15.6 ± 2.5 μg/g in corrected males vs. 15.7 ± 2.8 μg/g in heterozygotes). The results show that the Menkes defect in mice is corrected by the human Menkes gene and that adequate correction is obtained even when the transgene expression does not match that of the endogenous gene.

The brachyspira hyodysenteriae ftnA gene : DNA vaccination and real-time PCR quantification of bacteria in a mouse model of disease

The nucleotide sequence of the Brachyspira hyodysenteriae ftnA gene, encoding a putative ferritin protein (FtnA), was determined. Analysis of the sequence predicted that this gene encoded a protein of 180 amino acids. RT-PCR and Western blot showed that the ftnA gene was expressed in B. hyodysenteriae, and evidence suggests that FtnA stores iron rather than haem. ftnA was delivered as DNA and recombinant protein vaccines in a mouse model of B. hyodysenteriae infection. Vaccine efficacy was monitored by caecal pathology and quantification of B. hyodysenteriae numbers in the caeca of infected mice by real-time PCR.

Liver cell transplantation leads to repopulation and functional correction in a mouse model of Wilson's disease

Background and Aim: The toxic milk (tx) mouse is a non-fatal animal model for the metabolic liver disorder, Wilson's disease. The tx mouse has a mutated gene for a copper-transporting protein, causing early copper accumulation in the liver and late accumulation in other tissues. The present study investigated the efficacy of liver cell transplantation (LCT) to correct the tx mouse phenotype.

Methods: Congenic hepatocytes were isolated and intrasplenically transplanted into 3–4-month-old tx mice, which were then placed on various copper-loaded diets to examine its influence on repopulation by transplanted cells. The control animals were age-matched untransplanted tx mice. Liver repopulation was determined by comparisons of restriction fragment length polymorphism ratios (DNA and mRNA), and copper levels were measured by atomic absorption spectroscopy.

Results: Repopulation in recipient tx mice was detected in 11 of 25 animals (44%) at 4 months after LCT. Dietary copper loading (whether given before or after LCT, or both) provided no growth advantage for donor cells, with similar repopulation incidences in all copper treatment groups. Overall, liver copper levels were significantly lower in repopulated animals (538 ± 68 µg/g, n = 11) compared to non-repopulated animals (866 ± 62 µg/g, n = 14) and untreated controls (910 ± 103 µg/g, n = 6; P < 0.05). This effect was also seen in the kidney and spleen. Brain copper levels remained unchanged.

Conclusion: Transplanted liver cells can proliferate and correct a non-fatal metabolic liver disease, with some restoration of hepatic copper homeostasis after 4 months leading to reduced copper levels in the liver and extrahepatic tissues, but not in the brain.

Investigation of plasmodiophora brassicae (clubroot disease) in vegetable brassica using arabidopsis thaliana as a model system

Clubroot, caused by Plasmodiophora brassicae, is the most devastating soil-borne disease of vegetable brassicas. It occurs all over the world and is responsible for crop losses of up to 10% every year. In Australia, the disease is being managed effectively with chemicals and cultural practices, but ideally control can be improved in the long term by the introduction of resistant cultivars. The life cycle ofP. brassicae and mode of action of plant resistance has not been fully elucidated because of the technical difficulties of working with an obligate, soil-borne plant pathogen. However, Arabidopsis thaliana, which is a host ofP. brassicae, has great potential as a model system for studying the life cycle, the infection process and development of resistance. We have developed a sand-liquid-culture system for growing Arabidopsis that allows easy observation of all life stages and, most importantly, the primary plasmodial stages within the root hair. The method was first optimised for observations of the lifecycle of the pathogen in a susceptible Arabidopsis ecotype (Col-3) where all stages of the lifecycle have now been observed and characterised. Further screening of Arabidopsis ecotypes for disease resistance has utilised one of the most virulent Australian pathotypes of brassica (ECD number 16/19/31). To date, Arabidopsis ecotype Ta-0 has shown a level of tolerance to the disease even though the roots get infected. It has been reported earlier that resistance toP. brassicae in Arabidopsis is due to one or a small number of genes. To examine changes in gene expression during the early, critical stages of infection, RNA was extracted from the susceptible and resistant ecotypes at two time points, 4 days and 17 days after inoculation. Microarray analysis will be used to investigate genome wide changes in gene expression during infection but also to identify candidate genes that may confer resistance to Australian isolates of the pathogen.

Development and use of a model system to monitor clubroot disease progression with an Australian field collection of Plasmodiophora brassicae

A modified sand–liquid culture method facilitated easy visualisation of the primary life cycle stages of Plasmodiophora brassicae within clean root hairs of the Arabidopsis host. Pathogen penetration occurred from day 4 onwards and then primary plasmodia developed within the host root. Several Arabidopsis ecotypes tested in varying growth conditions showed differences in disease expression. Defined growth cabinet conditions were found most suitable for studying disease progression in the ecotypes and for achieving uniform infection and disease development. Arabidopsis ecotypes Ta-0 and Tsu-0 known to be partially resistant to a German single-spore isolate of P. brassicae were susceptible to an Australian (Victorian) field population of P. brassicae. The European clubroot differential test was used to confirm virulence and describe the pathotype of the Victorian field population. Knowledge of the interaction of an Australian population of P. brassicae with its host will provide valuable information on a disease which is very difficult to control.

Validation of model-based estimates (synthetic estimates) of the prevalence of risk factors for coronary heart disease for wards in England

Several sets of model-based estimates (synthetic estimates) of the prevalence of risk factors for coronary heart disease for small areas in England have been developed. These have been used in policy documents to indicate which areas are in need of intervention. In general, these models have not been subjected to validity assessment. This paper describes a validity assessment of 16 sets of synthetic estimates, by comparison of the models with national, regional and local survey-based estimates, and local mortality rate estimates. Model-based estimates of the prevalence of smoking, low fruit and vegetable consumption, obesity, hypertension and raised cholesterol are found to be valid.