Equitability revisited: why the “equitable threat score” is not equitable

In the forecasting of binary events, verification measures that are “equitable” were defined by Gandin and Murphy to satisfy two requirements: 1) they award all random forecasting systems, including those that always issue the same forecast, the same expected score (typically zero), and 2) they are expressible as the linear weighted sum of the elements of the contingency table, where the weights are independent of the entries in the table, apart from the base rate. The authors demonstrate that the widely used “equitable threat score” (ETS), as well as numerous others, satisfies neither of these requirements and only satisfies the first requirement in the limit of an infinite sample size. Such measures are referred to as “asymptotically equitable.” In the case of ETS, the expected score of a random forecasting system is always positive and only falls below 0.01 when the number of samples is greater than around 30. Two other asymptotically equitable measures are the odds ratio skill score and the symmetric extreme dependency score, which are more strongly inequitable than ETS, particularly for rare events; for example, when the base rate is 2% and the sample size is 1000, random but unbiased forecasting systems yield an expected score of around −0.5, reducing in magnitude to −0.01 or smaller only for sample sizes exceeding 25 000. This presents a problem since these nonlinear measures have other desirable properties, in particular being reliable indicators of skill for rare events (provided that the sample size is large enough). A potential way to reconcile these properties with equitability is to recognize that Gandin and Murphy’s two requirements are independent, and the second can be safely discarded without losing the key advantages of equitability that are embodied in the first. This enables inequitable and asymptotically equitable measures to be scaled to make them equitable, while retaining their nonlinearity and other properties such as being reliable indicators of skill for rare events. It also opens up the possibility of designing new equitable verification measures

Functional conservation of Pax6 regulatory elements in humans and mice demonstrated with a novel transgenic reporter mouse

<p>Abstract</p> <p>Background</p> <p>The Pax6 transcription factor is expressed during development in the eyes and in specific CNS regions, where it is essential for normal cell proliferation and differentiation. Mice lacking one or both copies of the <it>Pax6 </it>gene model closely humans with loss-of-function mutations in the <it>PAX6 </it>locus. The sequence of the Pax6/PAX6 protein is identical in mice and humans and previous studies have shown <it>structural </it>conservation of the gene's regulatory regions.</p> <p>Results</p> <p>We generated a transgenic mouse expressing green fluorescent protein (GFP) and neomycin resistance under the control of the entire complement of human <it>PAX6 </it>regulatory elements using a modified yeast artificial chromosome (YAC). Expression of GFP was studied in embryos from 9.5 days on and was confined to cells known to express Pax6. GFP expression was sufficiently strong that expressing cells could be distinguished from non-expressing cells using flow cytometry.</p> <p>Conclusion</p> <p>This work demonstrates the <it>functional </it>conservation of the regulatory elements controlling <it>Pax6/PAX6 </it>expression in mice and humans. The transgene provides an excellent tool for studying the functions of different <it>Pax6/PAX6 </it>regulatory elements in controlling Pax6 expression in animals that are otherwise normal. It will allow the analysis and isolation of cells in which <it>Pax6 </it>is activated, irrespective of the status of the endogenous locus.</p

The occupation of a box as a toy model for the seismic cycle of a fault

We illustrate how a simple statistical model can describe the quasiperiodic occurrence of large earthquakes. The model idealizes the loading of elastic energy in a seismic fault by the stochastic filling of a box. The emptying of the box after it is full is analogous to the generation of a large earthquake in which the fault relaxes after having been loaded to its failure threshold. The duration of the filling process is analogous to the seismic cycle, the time interval between two successive large earthquakes in a particular fault. The simplicity of the model enables us to derive the statistical distribution of its seismic cycle. We use this distribution to fit the series of earthquakes with magnitude around 6 that occurred at the Parkfield segment of the San Andreas fault in California. Using this fit, we estimate the probability of the next large earthquake at Parkfield and devise a simple forecasting strategy.Comment: Final version of the published paper, with an erratum and an unpublished appendix with some proof

European Mixed Forests: definition and research perspectives

peer-reviewedAim of study: We aim at (i) developing a reference definition of mixed forests in order to harmonize comparative research in mixed forests and (ii) briefly review the research perspectives in mixed forests. Area of study: The definition is developed in Europe but can be tested worldwide. Material and methods: Review of existent definitions of mixed forests based and literature review encompassing dynamics, management and economic valuation of mixed forests. Main results: A mixed forest is defined as a forest unit, excluding linear formations, where at least two tree species coexist at any developmental stage, sharing common resources (light, water, and/or soil nutrients). The presence of each of the component species is normally quantified as a proportion of the number of stems or of basal area, although volume, biomass or canopy cover as well as proportions by occupied stand area may be used for specific objectives. A variety of structures and patterns of mixtures can occur, and the interactions between the component species and their relative proportions may change over time. The research perspectives identified are (i) species interactions and responses to hazards, (ii) the concept of maximum density in mixed forests, (iii) conversion of monocultures to mixed-species forest and (iv) economic valuation of ecosystem services provided by mixed forests. Research highlights: The definition is considered a high-level one which encompasses previous attempts to define mixed forests. Current fields of research indicate that gradient studies, experimental design approaches, and model simulations are key topics providing new research opportunities.The networking in this study has been supported by COST Action FP1206 EuMIXFOR

Using Real-World Data to Guide Ustekinumab Dosing Strategies for Psoriasis: A Prospective Pharmacokinetic-Pharmacodynamic Study.

Variation in response to biologic therapy for inflammatory diseases, such as psoriasis, is partly driven by variation in drug exposure. Real-world psoriasis data were used to develop a pharmacokinetic/pharmacodynamic (PK/PD) model for the first-line therapeutic antibody ustekinumab. The impact of differing dosing strategies on response was explored. Data were collected from a UK prospective multicenter observational cohort (491 patients on ustekinumab monotherapy, drug levels, and anti-drug antibody measurements on 797 serum samples, 1,590 measurements of Psoriasis Area Severity Index (PASI)). Ustekinumab PKs were described with a linear one-compartment model. A maximum effect (Emax ) model inhibited progression of psoriatic skin lesions in the turnover PD mechanism describing PASI evolution while on treatment. A mixture model on half-maximal effective concentration identified a potential nonresponder group, with simulations suggesting that, in future, the model could be incorporated into a Bayesian therapeutic drug monitoring "dashboard" to individualize dosing and improve treatment outcomes

Controlled overexpression of Pax6 in vivo negatively autoregulates the Pax6 locus, causing cell-autonomous defects of late cortical progenitor proliferation with little effect on cortical arealization

Levels of expression of the transcription factor Pax6 vary throughout corticogenesis in a rostro-lateral(high) to caudo-medial(low) gradient across the cortical proliferative zone. Previous loss-of-function studies have indicated that Pax6 is required for normal cortical progenitor proliferation, neuronal differentiation, cortical lamination and cortical arealization, but whether and how its level of expression affects its function is unclear. We studied the developing cortex of PAX77 YAC transgenic mice carrying several copies of the human PAX6 locus with its full complement of regulatory regions. We found that PAX77 embryos express Pax6 in a normal spatial pattern, with levels up to three times higher than wild type. By crossing PAX77 mice with a new YAC transgenic line that reports Pax6 expression (DTy54), we showed that increased expression is limited by negative autoregulation. Increased expression reduces proliferation of late cortical progenitors specifically, and analysis of PAX77↔wild-type chimeras indicates that the defect is cell autonomous. We analyzed cortical arealization in PAX77 mice and found that, whereas the loss of Pax6 shifts caudal cortical areas rostrally, Pax6 overexpression at levels predicted to shift rostral areas caudally has very little effect. These findings indicate that Pax6 levels are stabilized by autoregulation, that the proliferation of cortical progenitors is sensitive to altered Pax6 levels and that cortical arealization is not

Osteoarthritis: 119. The Effectiveness of Exercise Therapy with and without Manual Therapy for Hip Osteoarthritis: A Multicentre Randomised Controlled Trial

Background: Current evidence indicates that exercise therapy (ET) has a short and medium-term benefit for hip osteoarthritis (OA), but evidence is inconclusive regarding the effect of manual therapy (MT). The primary aim of this randomised controlled trial was to determine the effectiveness of ET with and without MT on clinical outcomes for individuals with hip OA. A secondary aim was to ascertain the effect of an 8-week waiting period on outcomes. Methods: 131 men and women with hip OA recruited in four hospitals were initially randomised to one of three groups: ET (n = 45), a combination of ET and MT (n = 43) and wait-list control (n = 43). The two intervention groups underwent individualised ET or ET/MT for 8 weeks. Patients in the control group waited 8 weeks and were randomised to receive either ET or ET/MT after 9 week follow-up, and pooled with original treatment group data: ET (n = 66) and ET/ MT (n = 65). All participants were followed up at 9 and 18 weeks and the control group was reassessed at 27 weeks (18 weeks post-treatment) by the same blinded assessor. The primary outcome measure was the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC). Other outcomes included sit-to-stand, 50-foot walk test, pain severity, hip range of motion (ROM), anxiety, depression, quality of life (QOL), analgesic usage, physical activity, patient-perceived change and patient satisfaction. Intention-to-treat analysis was performed to determine within-group change and between-group differences for the three groups at baseline and 9 weeks, and the two treatment groups at baseline, 9 and 18 weeks. Results: Eight patients (6.1%) were lost to follow-up at 9 weeks and 19 (14.5%) were lost to follow-up by 18 weeks. Both ET (n = 66) and ET/MT groups (n = 65) showed significant within-group improvements in WOMAC, pain severity, sit-to-stand and HROM measures at 9 weeks, which were still evident at 18 weeks. There was no significant within-group change in anxiety, depression, QOL, analgesic usage, 50-foot walk test or physical activity. There was no significant difference between the two intervention groups for any of the outcomes. Regarding the results of the original ET, ET/MT and control group allocation, there was a significant improvement in one or both ET and ET/MT groups compared with the control group in the same outcomes, as well as patient perceived improvement at 9 weeks. There was no significant difference between the three groups in analgesic usage, WOMAC stiffness subscale, sit-to-stand and 50 foot walk tests, QOL and physical activity. There was an overall deterioration in anxiety and depression scores. Conclusions: The addition of MT to an 8 week programme of ET for hip OA resulted in similar improvements in pain, function and ROM at 9 and 18 weeks. The significant improvement which occurred in the same outcomes in the two treatment groups compared with a wait-list control of 8 weeks has implications for waiting list management Disclosure statement: The authors have declared no conflicts of interes

Small Platforms, High Return: The Need to Enhance Investment in Small Satellites for Focused Science, Career Development, and Improved Equity

In the next decade, there is an opportunity for very high return on investment of relatively small budgets by elevating the priority of smallsat funding in heliophysics. We've learned in the past decade that these missions perform exceptionally well by traditional metrics, e.g., papers/year/\$M (Spence et al. 2022 -- arXiv:2206.02968). It is also well established that there is a "leaky pipeline" resulting in too little diversity in leadership positions (see the National Academies Report at https://www.nationalacademies.org/our-work/increasing-diversity-in-the-leadership-of-competed-space-missions). Prioritizing smallsat funding would significantly increase the number of opportunities for new leaders to learn -- a crucial patch for the pipeline and an essential phase of career development. At present, however, there are far more proposers than the available funding can support, leading to selection ratios that can be as low as 6% -- in the bottom 0.5th percentile of selection ratios across the history of ROSES. Prioritizing SmallSat funding and substantially increasing that selection ratio are the fundamental recommendations being made by this white paper.Comment: White paper submitted to the Decadal Survey for Solar and Space Physics (Heliophysics) 2024-2033; 6 pages, 1 figur

Quantum state preparation and macroscopic entanglement in gravitational-wave detectors

Long-baseline laser-interferometer gravitational-wave detectors are operating at a factor of 10 (in amplitude) above the standard quantum limit (SQL) within a broad frequency band. Such a low classical noise budget has already allowed the creation of a controlled 2.7 kg macroscopic oscillator with an effective eigenfrequency of 150 Hz and an occupation number of 200. This result, along with the prospect for further improvements, heralds the new possibility of experimentally probing macroscopic quantum mechanics (MQM) - quantum mechanical behavior of objects in the realm of everyday experience - using gravitational-wave detectors. In this paper, we provide the mathematical foundation for the first step of a MQM experiment: the preparation of a macroscopic test mass into a nearly minimum-Heisenberg-limited Gaussian quantum state, which is possible if the interferometer's classical noise beats the SQL in a broad frequency band. Our formalism, based on Wiener filtering, allows a straightforward conversion from the classical noise budget of a laser interferometer, in terms of noise spectra, into the strategy for quantum state preparation, and the quality of the prepared state. Using this formalism, we consider how Gaussian entanglement can be built among two macroscopic test masses, and the performance of the planned Advanced LIGO interferometers in quantum-state preparation

Search for gravitational wave bursts in LIGO's third science run

We report on a search for gravitational wave bursts in data from the three LIGO interferometric detectors during their third science run. The search targets subsecond bursts in the frequency range 100-1100 Hz for which no waveform model is assumed, and has a sensitivity in terms of the root-sum-square (rss) strain amplitude of hrss ~ 10^{-20} / sqrt(Hz). No gravitational wave signals were detected in the 8 days of analyzed data.Comment: 12 pages, 6 figures. Amaldi-6 conference proceedings to be published in Classical and Quantum Gravit