The road to precision oncology

The ultimate goal of precision medicine is to use population-based molecular, clinical and other data to make individually tailored clinical decisions for patients, although the path to achieving this goal is not entirely clear. A new study shows how knowledge banks of patient data can be used to make individual treatment decisions in acute myeloid leukemia

Adenosine to inosine editing by ADAR2 requires formation of a ternary complex on the GluR-B R/G site

RNA editing by members of the ADAR (adenosine deaminase that acts on RNA) enzyme family involves hydrolytic deamination of adenosine to inosine within the context of a double-stranded pre-mRNA substrate. Editing of the human GluR-B transcript is catalyzed by, the enzyme ADAR2 at the Q/R and R/G sites. We have established a minimal RNA substrate for editing based on the RIG site and have characterized the interaction of ADAR2 with this RNA by gel shift, kinetic, and cross-linking analyses. Gel shift analysis revealed that two complexes are formed on the RNA as protein concentration is increased; the ADAR monomers can be crosslinked to one another in an RNA-dependent fashion. We performed a detailed kinetic study of the editing reaction; the data from this study are consistent with a reaction scheme in which formation of an ADAR2.RNA ternary complex is required for efficient RNA editing and in which formation of this complex is rate determining. These observations suggest that RNA adenosine deaminases function as homodimers on their RNA substrates and may partially explain regulation of RNA editing in these systems

Estimation of stochastic scale with best-worst data

Recently there has been a steady stream of literature advocating the best-worst response mechanism, where respondents are asked to sequentially choose the best and worst alternatives in a choice set, resulting in a partial or complete ranking of the alternatives. In this paper, we present an empirical study in which respondents were encouraged to respond using repeated best-worst, but were nonetheless free to respond in any order they preferred. Models are estimated that account for three alternative response processes: conventional ranking of the alternatives from best to worst, sequential best-worst choice, and two best choices followed by two worst choices. While the sequential best-worst models perform best, the sensitivities retrieved are consistent across all three models. We find strong evidence of stochastic scale heterogeneity across respondents, where the extent of this heterogeneity is also consistent across all three model forms. However, deterministic scale heterogeneity, that accounts for differences in scale across each of the pseudo-observations, is not consistent across the model forms, with respect to the implied rank of the observation. Rather, the consistency is with the number of alternatives associated with the pseudo-observation, with scale decreasing as the number of alternatives decreases. A test of alternative specifications of the panel in the mixture model used to identify stochastic scale identifies that scale should be invariant across the full set of responses by an individual, rather than just the responses from each rank from that individual. Despite an overall finding that the sensitivities retrieved are robust to the assumption of the completion order of the ranking within the model, differences in sensitivities retrieved from each best-worst choice raise concerns with pooling the data across best-worst choices, in line with concerns raised previously with rankings data

Interactive stated choice surveys: A study of air travel behaviour

Stated preference (SP) experiments are becoming an increasingly popular survey methodology for investigating air travel choice behaviour. Nevertheless, some evidence suggests that SP experiments do not mirror decisions in real markets. In this paper we introduce a novel survey methodology that aims to make air travel surveys more consistent with real world settings, with the aim of obtaining more realistic results. The survey is modelled on the interface and functionality of an online travel agent (OTA). As with a real OTA, many ticket options are presented. Sort tools allow the options to be reordered, search tools allow options to be removed from consideration, and a further tool allows attributes to be hidden and shown. Extensive use of these tools is made by the 462 respondents, with the captured data revealing some attribute preferences at the individual level, and significant heterogeneity of preference across individuals. A traditional SP component was also completed by the respondents. Our exploratory analysis as well as random utility model estimation results confirm not only that respondents seem to engage more actively with the interactive survey, but also that the resulting data allows for better performance in model estimation. These results have implications for the study of other complex travel choices where interactive surveys may similarly be preferable to standard approaches

Search based internet surveys: Airline stated choice

Stated preference (SP) experiments are becoming an increasingly popular survey methodology for investigating air travel choice behaviour. Nevertheless, some evidence suggests that SP experiments do not mirror decisions in real markets. In this paper we introduce a novel survey methodology that aims to make air travel surveys more consistent with real world settings, with the aim of obtaining more realistic results. The survey is modelled on the interface and functionality of an online travel agent (OTA). As with a real OTA, many ticket options are presented. Sort tools allow the options to be reordered, search tools allow options to be removed from consideration, and a further tool allows attributes to be hidden and shown. Extensive use of these tools is made by the 462 respondents, with the captured data revealing some attribute preferences at the individual level, and significant heterogeneity of preference across individuals. A traditional SP component was also completed by the respondents. Mixed multinomial logit models were estimated on data from both the traditional SP and OTA components, with the later exhibiting greater willingness to pay (WTP) heterogeneity

Investors' Reactions to Management Earnings Forecasts: The Effects of Changes in Forecast Precision and Investor Preferences

This study examines the effects of changes in management earnings forecast precision (i.e., changes in the width of the forecast range) and investor preferences on investor judgments. In general, prior research finds that more precise management forecasts are more credible than less precise management forecasts (e.g., Baginski et al. 1993). Nevertheless, when economic uncertainty is high, investors do not prefer very precise forecasts over less precise forecasts (Du et al. 2011). Based on the concept of credibility from Mercer (2005) and motivated reasoning theory from Kunda (1990), I predict that investors’ reactions to changes in forecast specificity will be based on their preferences for firm performance. Specifically, I predict that investors holding a long position will judge management to be more competent when the forecast range narrows, but more trustworthy when the forecast range widens. In contrast, I predict that investors holding a short position will judge management to be less trustworthy when the forecast range narrows, but less competent when the forecast range widens. I use an experiment to test these predictions. While results do not support the predictions above, I do find evidence that: (1) changes in forecast specificity affect investors’ judgments of economic uncertainty, and (2) investors’ perceptions of managerial trustworthiness and competence have predictable consequences for firm management. Specifically, in regard to the former, I find that investors perceive the greatest increase in economic uncertainty when holding a long position and the forecast range widens; conversely, I find that investors perceive a decrease in economic uncertainty when holding a short position and the forecast range narrows. In regard to the consequences of managerial credibility, I find investors’ belief that the manager is manipulating earnings is decreasing in perceived managerial trustworthiness. In addition, I find that investors’ willingness to retain the CEO is increasing in perceived managerial competence, but, after controlling for perceived managerial competence, investors’ decision to retain the CEO is not reliably related to perceived managerial trustworthiness

Understanding Buy in for Risky Prospects: Incorporating Degree of Belief into the ex ante Assessment of Support for Alternative Road Pricing Schemes

This paper investigates support for road pricing reform within the framework of a referendum voting choice model. Central to this task is how to identify ex ante support for specific road pricing schemes, such that the evidence is believable. Our approach is centred on a referendum voting choice model for alternative road pricing schemes in which we incorporate information that accounts for the degree of belief of the extent to which such schemes will make voters better or worse off. We find that accounting for belief in the benefits results in sizeable reductions in the sensitivity to the levels of the charge but quite small impacts on the sensitivity to revenue allocation.Australian Research Council Discovery Progra

Exonuclease activity and P nucleotide addition in the generation of the expressed immunoglobulin repertoire

BACKGROUND: Immunoglobulin rearrangement involves random and imprecise processes that act to both create and constrain diversity. Two such processes are the loss of nucleotides through the action of unknown exonuclease(s) and the addition of P nucleotides. The study of such processes has been compromised by difficulties in reliably aligning immunoglobulin genes and in the partitioning of nucleotides between segment ends, and between N and P nucleotides. RESULTS: A dataset of 294 human IgM sequences was created and partitioned with the aid of a probabilistic model. Non-random removal of nucleotides is seen between the three IGH gene types with the IGHV gene averaging removals of 1.2 nucleotides compared to 4.7 for the other gene ends (p < 0.001). Individual IGHV, IGHD and IGHJ gene subgroups also display statistical differences in the level of nucleotide loss. For example, within the IGHJ group, IGHJ3 has average removals of 1.3 nucleotides compared to 6.4 nucleotides for IGHJ6 genes (p < 0.002). Analysis of putative P nucleotides within the IgM and pooled datasets revealed only a single putative P nucleotide motif (GTT at the 3' D-REGION end) to occur at a frequency significantly higher then would be expected from random N nucleotide addition. CONCLUSIONS: The loss of nucleotides due to the action of exonucleases is not random, but is influenced by the nucleotide composition of the genes. P nucleotides do not make a significant contribution to diversity of immunoglobulin sequences. Although palindromic sequences are present in 10% of immunologlobulin rearrangements, most of the 'palindromic' nucleotides are likely to have been inserted into the junction during the process of N nucleotide addition. P nucleotides can only be stated with confidence to contribute to diversity of less than 1% of sequences. Any attempt to identify P nucleotides in immunoglobulins is therefore likely to introduce errors into the partitioning of such sequences

Blaming Bill Gates AGAIN! Misuse, overuse and misunderstanding of performance data in sport

Recently in Sport, Education and Society, Williams and Manley (2014) argued against the heavy reliance on technology in professional Rugby Union and elite sport in general. In summary, technology is presented as an elitist, ‘gold standard’ villain that management and coaches use to exert control and by which players lose autonomy, identity, motivation, social interactions and expertise. In this article we suggest that the sociological interpretations and implications offered by Williams and Manley may be somewhat limited when viewed in isolation. In doing so, we identify some core methodological issues in Williams and Manley’s study and critically consider important arguments for utilising technology; notably, to inform coach decision making and generate player empowerment. Secondly, we present a different, yet perhaps equally concerning, practice-oriented interpretation of the same results but from alternative coaching and expertise literature. Accordingly, we suggest that Williams and Manley have perhaps raised their alarm prematurely, inappropriately and on somewhat shaky foundations. We also hope to stimulate others to consider contrary positions, or at least to think about this topic in greater detail. More specifically, we encourage coaches and academics to think carefully about what technology is employed, how and why, and then the means by which these decisions are discussed with and, preferably, sold to players. Certainly, technology can significantly enhance coach decision making and practice, while also helping players to optimise their focus, empowerment and independence in knowing how to achieve their personal and collective goals