Infection status outcome, machine learning method and virus type interact to affect the optimised prediction of hepatitis virus immunoassay results from routine pathology laboratory assays in unbalanced data

BACKGROUND: Advanced data mining techniques such as decision trees have been successfully used to predict a variety of outcomes in complex medical environments. Furthermore, previous research has shown that combining the results of a set of individually trained trees into an ensemble-based classifier can improve overall classification accuracy. This paper investigates the effect of data pre-processing, the use of ensembles constructed by bagging, and a simple majority vote to combine classification predictions from routine pathology laboratory data, particularly to overcome a large imbalance of negative Hepatitis B virus (HBV) and Hepatitis C virus (HCV) cases versus HBV or HCV immunoassay positive cases. These methods were illustrated using a never before analysed data set from ACT Pathology (Canberra, Australia) relating to HBV and HCV patients. RESULTS: It was easier to predict immunoassay positive cases than negative cases of HBV or HCV. While applying an ensemble-based approach rather than a single classifier had a small positive effect on the accuracy rate, this also varied depending on the virus under analysis. Finally, scaling data before prediction also has a small positive effect on the accuracy rate for this dataset. A graphical analysis of the distribution of accuracy rates across ensembles supports these findings. CONCLUSIONS: Laboratories looking to include machine learning as part of their decision support processes need to be aware that the infection outcome, the machine learning method used and the virus type interact to affect the enhanced laboratory diagnosis of hepatitis virus infection, as determined by primary immunoassay data in concert with multiple routine pathology laboratory variables. This awareness will lead to the informed use of existing machine learning methods, thus improving the quality of laboratory diagnosis via informatics analyses

It’s all foreign to me: learning through the language of genetics and molecular biology

Molecular Biology and Genetics are taught to undergraduate students at the second and third year level of their University of Canberra degrees. The assumption is, particularly for the third year students who have passed previous units/subjects in fundamental chemistry, biology and biochemistry, that the concepts and many of the details confronted in the more specialised discipline areas like genetics/molecular biology will be familiar. Anecdotally, this has not been true and the specialised language, for a majority of students, leads to a loss of engagement with the content of the unit and hence the learning outcomes. While there are issues around retention of knowledge from previously studied foundation units, it seems a bigger problem is that students find the lecture material, readings and other study material impenetrable

Activating multiple senses in learning Statistics

Introduction to Statistics at the University of Canberra (UC) is a service unit taken by students from a variety of disciplines. However, it is common for students to dislike and under-perform in Statistics. We sought to address these issues by redesigning the way that Statistics is taught. Given the importance of acquiring statistical language to learning Statistics, we decided to employ language learning techniques in Statistics classes. The project brought together a statistician and an educational expert to reconceptualise the syllabus, and focused on developing different methods of delivery. New teaching materials including online exercises and new ways of delivery involving multiple senses of hearing, speaking and moving were designed and produced, placing greater emphasis on applying statistics and interpreting data. Two cohorts of students were evaluated, the control cohort (CG, 2007 Semester 1) with a traditional teaching style, and the experimental cohort (EG) taught with non-traditional methods, as summarised above (2008 Semester 1). Students in EG showed a greater improvement in defining key concepts such as population and standard deviation and have improved attitudes towards the role of statistics to their disciplines and performed significantly better in class tests and examinations

One potato, two potato, three potato, four: the use of Hot Potatoes software in science language comprehension

Our paper concentrates on innovation in teaching two ‘hard’ sciences, namely Genetics and Statistics. Reform in the teaching of Statistics moved through the higher education sector in Australia in the 1990s. Emphasis was placed on statistical thinking and active learning rather than recipes and derivations. New-style textbooks and laboratory manuals were published that employed teaching techniques from a variety of disciplines, but not from language teaching. Teaching in Genetics, generally, is in a transmissive style and as the language of Genetics is as foreign as a foreign language, texts written become inaccessible to many students. An earlier study (Zhang and Lidbury 2006) has examined a range of language techniques in the teaching of tertiary Genetics and Molecular Biology, and has recently focussed on language learning via the Hot Potatoes software. For this original study, Hot Potatoes was used as one of a suite of language-centred teaching approaches, so its full value has not, thus far, been individually assessed. Anecdotally, Hot Potatoes was a great tool to revise genetic language from previous lectures, and was appreciated by motivated students who wished to explore extra voluntary online exercises, or use the Hot Potatoes exercises as study tools. This study in Statistics will focus primarily on Hot Potatoes and assess it as a tool through which to teach statistical language

Identification and characterization of a Ross River virus variant that grows persistently in macrophages, shows altered disease kinetics in a mouse model, and exhibits resistance to type I interferon

Alphaviruses, such as chikungunya virus, o'nyong-nyong virus, and Ross River virus (RRV), cause outbreaks of human rheumatic disease worldwide. RRV is a positive-sense single-stranded RNA virus endemic to Australia and Papua New Guinea. In this study, we sought to establish an in vitro model of RRV evolution in response to cellular antiviral defense mechanisms. RRV was able to establish persistent infection in activated macrophages, and a small-plaque variant (RRVPERS) was isolated after several weeks of culture. Nucleotide sequence analysis of RRV PERS found several nucleotide differences in the nonstructural protein (nsP) region of the RRV PERS genome. A point mutation was also detected in the E2 gene. Compared to the parent virus (RRV-T48), RRV PERS showed significantly enhanced resistance to beta interferon (IFN-β)-stimulated antiviral activity. RRV PERS infection of RAW 264.7 macrophages induced lower levels of IFN-β expression and production than infection with RRV-T48. RRV PERS was also able to inhibit type I IFN signaling. Mice infected with RRV PERS exhibited significantly enhanced disease severity and mortality compared to mice infected with RRV-T48. These results provide strong evidence that the cellular antiviral response can direct selective pressure for viral sequence evolution that impacts on virus fitness and sensitivity to alpha/beta IFN (IFN-α/β).Facultad de Ciencias Exacta

Arthritogenic alphaviral infection perturbs osteoblast function and triggers pathologic bone loss

Arthritogenic alphaviruses including Ross River virus (RRV), Sindbis virus, and chikungunya virus cause worldwide outbreaks of musculoskeletal disease. The ability of alphaviruses to induce bone pathologies remains poorly defined. Here we show that primary human osteoblasts (hOBs) can be productively infected by RRV. RRV-infected hOBs produced high levels of inflammatory cytokine including IL-6. The RANKL/OPG ratio was disrupted in the synovial fluid of RRV patients, and this was accompanied by an increase in serum Tartrate-resistant acid phosphatase 5b (TRAP5b) levels. Infection of bone cells with RRV was validated using an established RRV murine model. In wild-type mice, infectious virus was detected in the femur, tibia, patella, and foot, together with reduced bone volume in the tibial epiphysis and vertebrae detected by microcomputed tomographic (μCT) analysis. The RANKL/OPG ratio was also disrupted in mice infected with RRV; both this effect and the bone loss were blocked by treatment with an IL-6 neutralizing antibody. Collectively, these findings provide previously unidentified evidence that alphavirus infection induces bone loss and that OBs are capable of producing proinflammatory mediators during alphavirus-induced arthralgia. The perturbed RANKL/OPG ratio in RRV-infected OBs may therefore contribute to bone loss in alphavirus infection

Weighting of orthostatic intolerance time measurements with standing difficulty score stratifies ME/CFS symptom severity and analyte detection

Background. Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is clinically defined and characterised by persistent disabling tiredness and exertional malaise, leading to functional impairment. Methods. This study introduces the weighted standing time (WST) as a proxy for ME/CFS severity, and investigates its behaviour in an Australian cohort. WST was calculated from standing time and subjective standing difficulty data, collected via orthostatic intolerance assessments. The distribution of WST for healthy controls and ME/CFS patients was correlated with the clinical criteria, as well as pathology and cytokine markers. Included in the WST cytokine analyses were activins A and B, cytokines causally linked to inflammation, and previously demonstrated to separate ME/CFS from healthy controls. Forty-five ME/CFS patients were recruited from the CFS Discovery Clinic (Victoria) between 2011 and 2013. Seventeen healthy controls were recruited concurrently and identically assessed. Results. WST distribution was significantly different between ME/CFS participants and controls, with six diagnostic criteria, five analytes and one cytokine also significantly different when comparing severity via WST. On direct comparison of ME/CFS to study controls, only serum activin B was significantly elevated, with no significant variation observed for a broad range of serum and urine markers, or other serum cytokines. Conclusions. The enhanced understanding of standing test behaviour to reflect orthostatic intolerance as a ME/CFS symptom, and the subsequent calculation of WST, will encourage the greater implementation of this simple test as a measure of ME/CFS diagnosis, and symptom severity, to the benefit of improved diagnosis and guidance for potential treatments

Identification and characterization of a Ross River virus variant that grows persistently in macrophages, shows altered disease kinetics in a mouse model, and exhibits resistance to type I interferon

Alphaviruses, such as chikungunya virus, o'nyong-nyong virus, and Ross River virus (RRV), cause outbreaks of human rheumatic disease worldwide. RRV is a positive-sense single-stranded RNA virus endemic to Australia and Papua New Guinea. In this study, we sought to establish an in vitro model of RRV evolution in response to cellular antiviral defense mechanisms. RRV was able to establish persistent infection in activated macrophages, and a small-plaque variant (RRVPERS) was isolated after several weeks of culture. Nucleotide sequence analysis of RRV PERS found several nucleotide differences in the nonstructural protein (nsP) region of the RRV PERS genome. A point mutation was also detected in the E2 gene. Compared to the parent virus (RRV-T48), RRV PERS showed significantly enhanced resistance to beta interferon (IFN-β)-stimulated antiviral activity. RRV PERS infection of RAW 264.7 macrophages induced lower levels of IFN-β expression and production than infection with RRV-T48. RRV PERS was also able to inhibit type I IFN signaling. Mice infected with RRV PERS exhibited significantly enhanced disease severity and mortality compared to mice infected with RRV-T48. These results provide strong evidence that the cellular antiviral response can direct selective pressure for viral sequence evolution that impacts on virus fitness and sensitivity to alpha/beta IFN (IFN-α/β).Facultad de Ciencias Exacta

Lessons from Toxicology: Developing a 21st‑Century Paradigm for Medical Research

Biomedical developments in the 21st century provide an unprecedented opportunity to gain a dynamic systems-level and human-specific understanding of the causes and pathophysiologies of disease. This understanding is a vital need, in view of continuing failures in health research, drug discovery, and clinical translation. The full potential of advanced approaches may not be achieved within a 20th-century conceptual framework dominated by animal models. Novel technologies are being integrated into environmental health research and are also applicable to disease research, but these advances need a new medical research and drug discovery paradigm to gain maximal benefits. We suggest a new conceptual framework that repurposes the 21st-century transition underway in toxicology. Human disease should be conceived as resulting from integrated extrinsic and intrinsic causes, with research focused on modern human-specific models to understand disease pathways at multiple biological levels that are analogous to adverse outcome pathways in toxicology. Systems biology tools should be used to integrate and interpret data about disease causation and pathophysiology. Such an approach promises progress in overcoming the current roadblocks to understanding human disease and successful drug discovery and translation. A discourse should begin now to identify and consider the many challenges and questions that need to be solved