Graphical Aids to the Estimation and Discrimination of Uncertain Numerical Data

This research investigates the performance of graphical dot arrays designed to make discrimination of relative numerosity as effortless as possible at the same time as making absolute (quantitative) numerosity estimation as effortful as possible. Comparing regular, random, and hybrid (randomized regular) configurations of dots, the results indicate that both random and hybrid configurations reduce absolute numerosity estimation precision, when compared with regular dots arrays. However, discrimination of relative numerosity is significantly more accurate for hybrid dot arrays than for random dot arrays. Similarly, human subjects report significantly lower levels of subjective confidence in judgments when using hybrid dot configurations as compared with regular configurations; and significantly higher levels of subjective confidence as compared with random configurations. These results indicate that data graphics based on the hybrid, randomized-regular configurations of dots are well-suited to applications that require decisions to be based on numerical data in which the absolute quantities are less certain than the relative values. Examples of such applications include decision-making based on the outputs of empirically-based mathematical models, such as health-related policy decisions using data from predictive epidemiological models.     

Cell Signaling-Based Classifier Predicts Response to Induction Therapy in Elderly Patients with Acute Myeloid Leukemia

Single-cell network profiling (SCNP) data generated from multi-parametric flow cytometry analysis of bone marrow (BM) and peripheral blood (PB) samples collected from patients >55 years old with non-M3 AML were used to train and validate a diagnostic classifier (DX_SCNP) for predicting response to standard induction chemotherapy (complete response [CR] or CR with incomplete hematologic recovery [CRi] versus resistant disease [RD]). SCNP-evaluable patients from four SWOG AML trials were randomized between Training (N = 74 patients with CR, CRi or RD; BM set = 43; PB set = 57) and Validation Analysis Sets (N = 71; BM set = 42, PB set = 53). Cell survival, differentiation, and apoptosis pathway signaling were used as potential inputs for DX_SCNP. Five DX_SCNP classifiers were developed on the SWOG Training set and tested for prediction accuracy in an independent BM verification sample set (N = 24) from ECOG AML trials to select the final classifier, which was a significant predictor of CR/CRi (area under the receiver operating characteristic curve AUROC = 0.76, p = 0.01). The selected classifier was then validated in the SWOG BM Validation Set (AUROC = 0.72, p = 0.02). Importantly, a classifier developed using only clinical and molecular inputs from the same sample set (DX_CLINICAL2) lacked prediction accuracy: AUROC = 0.61 (p = 0.18) in the BM Verification Set and 0.53 (p = 0.38) in the BM Validation Set. Notably, the DX_SCNP classifier was still significant in predicting response in the BM Validation Analysis Set after controlling for DX_CLINICAL2 (p = 0.03), showing that DX_SCNP provides information that is independent from that provided by currently used prognostic markers. Taken together, these data show that the proteomic classifier may provide prognostic information relevant to treatment planning beyond genetic mutations and traditional prognostic factors in elderly AML.     

Cranial Morphology of the Brachystelechid ‘Microsaur’ Quasicaecilia texana Carroll Provides New Insights into the Diversity and Evolution of Braincase Morphology in Recumbirostran ‘Microsaurs’

Recumbirostran ‘microsaurs,’ a group of early tetrapods from the Late Carboniferous and Early Permian, are the earliest known example of adaptation to head-first burrowing in the tetrapod fossil record. However, understanding of the diversity of fossorial adaptation within the Recumbirostra has been hindered by poor anatomical knowledge of the more divergent forms within the group. Here we report the results of μCT study of Quasicaecilia texana, a poorly-known recumbirostran with a unique, broad, shovel-like snout. The organization of the skull roof and braincase of Quasicaecilia is found to be more in line with that of other recumbirostrans than previously described, despite differences in overall shape. The braincase is found to be broadly comparable to Carrolla craddocki, with a large presphenoid that encompasses much of the interorbital septum and the columella ethmoidalis, and a single compound ossification encompassing the sphenoid, otic, and occipital regions. The recumbirostran braincase conserves general structure and topology of braincase regions and cranial nerve foramina, but it is highly variable in the number of ossifications and their extent, likely associated with the reliance on braincase ossifications to resist compression during sediment compaction and mechanical manipulation by epaxial and hypaxial musculature. Expansion of the deep ventral neck musculature in Quasicaecilia, autapomorphic among recumbirostrans, may reflect unique biomechanical function, and underscores the importance of future attention to the role of the cervical musculature in contextualizing the origin and evolution of fossoriality in recumbirostrans.     

Merging Children’s Oncology Group Data with an External Administrative Database Using Indirect Patient Identifiers: A Report from the Children’s Oncology Group

Purpose

Clinical trials data from National Cancer Institute (NCI)-funded cooperative oncology group trials could be enhanced by merging with external data sources. Merging without direct patient identifiers would provide additional patient privacy protections. We sought to develop and validate a matching algorithm that uses only indirect patient identifiers.

Methods

We merged the data from two Phase III Children’s Oncology Group (COG) trials for de novo acute myeloid leukemia (AML) with the Pediatric Health Information Systems (PHIS). We developed a stepwise matching algorithm that used indirect identifiers including treatment site, gender, birth year, birth month, enrollment year and enrollment month. Results from the stepwise algorithm were compared against the direct merge method that used date of birth, treatment site, and gender. The indirect merge algorithm was developed on AAML0531 and validated on AAML1031.

Results

Of 415 patients enrolled on the AAML0531 trial at PHIS centers, we successfully matched 378 (91.1%) patients using the indirect stepwise algorithm. Comparison to the direct merge result suggested that 362 (95.7%) matches identified by the indirect merge algorithm were concordant with the direct merge result. When validating the indirect stepwise algorithm using the AAML1031 trial, we successfully matched 157 out of 165 patients (95.2%) and 150 (95.5%) of the indirectly merged matches were concordant with the directly merged matches.

Conclusions

These data demonstrate that patients enrolled on COG clinical trials can be successfully merged with PHIS administrative data using a stepwise algorithm based on indirect patient identifiers. The merged data sets can be used as a platform for comparative effectiveness and cost effectiveness studies.     

Do urban canyons influence street level grass pollen concentrations?

In epidemiological studies, outdoor exposure to pollen is typically estimated using rooftop monitoring station data, whilst exposure overwhelmingly occurs at street level. In this study the relationship between street level and roof level grass pollen concentrations was investigated for city centre street canyon environments in Aarhus, Denmark, and London, UK, during the grass pollen seasons of 2010 and 2011 respectively. For the period mid-day to late evening, street level concentrations in both cities tended to be lower than roof-level concentrations, though this difference was found to be statistically significant only in London. The ratio of street/roof level concentrations was compared with temperature, relative humidity, wind speed and direction, and solar radiation. Results indicated that the concentration ratio responds to wind direction with respect to relative canyon orientation and local source distribution. In the London study, an increase in relative humidity was linked to a significant decrease in street/roof level concentration ratio, and a possible causative mechanism involving moisture mediated pollen grain buoyancy is proposed. Relationships with the other weather variables were not found to be significant in either location. These results suggest a tendency for monitoring station data to overestimate exposure in the canyon environment.     

HDAC-mediated control of ERK- and PI3K-dependent TGF-β-induced extracellular matrix-regulating genes

Histone deacetylases (HDACs) regulate the acetylation of histones in the control of gene expression. Many non-histone proteins are also targeted for acetylation, including TGF-β signalling pathway components such as Smad2, Smad3 and Smad7. Our studies in mouse C3H10T1/2 fibroblasts suggested that a number of TGF-β-induced genes that regulate matrix turnover are selectively regulated by HDACs. Blockade of HDAC activity with trichostatin A (TSA) abrogated the induction of a disintegrin and metalloproteinase 12 (Adam12) and tissue inhibitor of metalloproteinases-1 (Timp-1) genes by TGF-β, whereas plasminogen activator inhibitor-1 (Pai-1) expression was unaffected. Analysis of the activation of cell signalling pathways demonstrated that TGF-β induced robust ERK and PI3K activation with delayed kinetics compared to the phosphorylation of Smads. The TGF-β induction of Adam12 and Timp-1 was dependent on such non-Smad signalling pathways and, importantly, HDAC inhibitors completely blocked their activation without affecting Smad signalling. Analysis of TGF-β-induced Adam12 and Timp-1 expression and ERK/PI3K signalling in the presence of semi-selective HDAC inhibitors valproic acid, MS-275 and apicidin implicated a role for class I HDACs. Furthermore, depletion of HDAC3 by RNA interference significantly down-regulated TGF-β-induced Adam12 and Timp-1 expression without modulating Pai-1 expression. Correlating with the effect of HDAC inhibitors, depletion of HDAC3 also blocked the activation of ERK and PI3K by TGF-β. Collectively, these data confirm that HDACs, and in particular HDAC3, are required for activation of the ERK and PI3K signalling pathways by TGF-β and for the subsequent gene induction dependent on these signalling pathways.     

Addressing PXR liabilities of phthalazine-based hedgehog/smoothened antagonists using novel pyridopyridazines

Pyridopyridazine antagonists of the hedgehog signaling pathway are described. Designed to optimize our previously described phthalazine smoothened antagonists, a representative compound eliminates a PXR liability while retaining potency and in vitro metabolic stability. Moreover, the compound has improved efficacy in a hedgehog/smoothened signaling mouse pharmacodynamic model.