Pseudodiagnosticity and preference hierarchy in a search-only inference paradigm.

Bayes' Theorem provides a rationality-standard for information search when there are two mutually exclusive hypotheses and one or more statistical cues pertaining to the likelihoods of the hypotheses. Prior research shows that when people already have a cue pertaining to a hypothesis and are asked to seek additional information to help decide which hypothesis is correct, they tend to exhibit a specific form of pseudodiagnosticity: Rather than seek information that would assess the same cue relative to an alternative hypothesis, they tend to seek information about how a second cue would pertain to the first hypothesis. For example, if people are told that 70% of genuine paintings are landscapes, they then seek to know the percentage of genuine paintings that are watercolor rather than the percentage of fake paintings that are landscapes. However, this response pattern has sometimes been violated in a way that may depend on the cues' numerical values (e.g., 70% vs. 30%), thus raising a question as to the nature of the bias: Does the selection bias characterize the search process per se, or does it reflect the manner in which people utilize already-obtained percentage information? To address these issues, we employed a novel, search-only judgment paradigm in which people were asked to search for cues and to select them without ever obtaining the cues' percentage values. The results confirmed a tendency toward same-hypothesis pseudodiagnosticity both in primary (i.e., most-preferred) and secondary preference, and supported a model in which pseudodiagnosticity can proceed with or without numerical cue data.

Cost Effectiveness of Cognitive Behavioral Therapy for the Treatment of Subjective Tinnitus in Australia.

OBJECTIVES: The aim of this study was to conduct an economic evaluation for the treatment of subjective tinnitus using different modalities of cognitive behavioral therapy (CBT) in Australia. DESIGN: A decision tree model was used to conduct a cost-utility analysis for CBT to determine the cost effectiveness for tinnitus treatments, in terms of cost per responder and cost per quality-adjusted life-year (QALY), from a health system perspective using a 2-year time horizon. Meta-analysis was used to differentiate the levels of effectiveness between three delivery methods for CBT: individual face-to-face care (fCBT), group sessions (gCBT), and a supported internet program (iCBT). One-way sensitivity analysis and probabilistic sensitivity analysis (PSA) explored the uncertainty surrounding model inputs and outcomes. Results were presented as incremental cost-effectiveness ratios compared with no treatment, and as net monetary benefit at a $50,000 willingness-to-pay threshold. RESULTS: Compared with no treatment, the incremental cost per responder was $700 for gCBT, $871 for iCBT, and $1380 for fCBT. The base case incremental cost-effectiveness ratio was $35,363 per QALY for fCBT, $17,935 per QALY for gCBT, and $22,321 per QALY for iCBT compared with no treatment, although there was substantial uncertainty around the QALY gain for responders. Net monetary benefit was $356 (fCBT), $555 (gCBT), and $487 (iCBT), indicating the treatments were cost effective compared with no treatment. One-way sensitivity analysis revealed the results were most sensitive to the probability of a positive response to treatment and treatment length. The PSA found the probability of being cost effective compared with no treatment for gCBT was 99.8%, iCBT 98.4%, and fCBT 71.5% at a willingness-to-pay of $50,000 per QALY, although QALY gain remained at a fixed value in the PSA. CONCLUSIONS: CBT for tinnitus was likely to be cost effective compared with no treatment regardless of treatment modality, assuming they are not mutually exclusive. Of the interventions, gCBT was the lowest cost per responder and lowest cost per QALY. Internet CBT obtained comparable economic outcomes due to similar treatment effectiveness and cost. Group CBT and iCBT warrant greater adoption in clinical practice for the treatment of subjective tinnitus. Further research on preference-based utility measures for varying levels of tinnitus severity and the durability of treatment effect is required to enhance the quality of economic evaluation in this field.

Biasing the input: A yoked-scientist demonstration of the distorting effects of optional stopping on Bayesian inference.

Prior work by Michael R. Dougherty and colleagues (Yu et al., 2014) shows that when a scientist monitors the p value during data collection and uses a critical p as the signal to stop collecting data, the resulting p is distorted due to Type I error-rate inflation. They argued similarly that the use of a critical Bayes factor (BF(crit)) for stopping distorts the obtained Bayes factor (BF), a position that has met with controversy. The present paper clarified that when BF(crit) is used as a stopping criterion, the sample becomes biased in that data consistent with large effects have a greater chance to be included than do other data, thus biasing the input to Bayesian inference. We report simulations of yoked pairs of scientists in which Scientist A uses BF(crit) to optionally stop, while Scientist B, sampling from the same population, stops when A stops. Thus, optional stopping is compared not to a hypothetical in which no stopping occurs, but to a situation in which B stops for reasons unrelated to the characteristics of B's sample. The results indicated that optional stopping biased the input for Bayesian inference. We also simulated the use of effect-size stabilization as a stopping criterion and found no bias in that case.

Expression and function of cell adhesion molecules during neural crest migration.

Neural crest cells are highly migratory cells that give rise to many derivatives including peripheral ganglia, craniofacial structures and melanocytes. Neural crest cells migrate along defined pathways to their target sites, interacting with each other and their environment as they migrate. Cell adhesion molecules are critical during this process. In this review we discuss the expression and function of cell adhesion molecules during the process of neural crest migration, in particular cadherins, integrins, members of the immunoglobulin superfamily of cell adhesion molecules, and the proteolytic enzymes that cleave these cell adhesion molecules. The expression and function of these cell adhesion molecules and proteases are compared across neural crest emigrating from different axial levels, and across different species of vertebrates.

The proto-oncogene Ret is required for male foetal germ cell survival.

The spermatogenic and oogenic lineages originate from bipotential primordial germ cells in response to signalling in the foetal testis or ovary, respectively. The signals required for male germ cell commitment and their entry into mitotic arrest remain largely unknown. Recent data show that the ligand GDNF is up regulated in the foetal testis indicating that it may be involved in male germ cell development. In this study genetic analysis of GDNF-RET signalling shows that RET is required for germ cell survival. Affected germ cells in Ret-/- mice lose expression of key germ cell markers, abnormally express cell cycle markers and undergo apoptosis. Surprisingly, a similar phenotype was not detected in Gdnf-/- mice indicating that either redundancy with a Gdnf related gene might compensate for its loss, or that RET operates in a GDNF independent manner in mouse foetal germ cells. Either way, this study identifies the proto-oncogene RET as a novel component of the foetal male germ cell development pathway.

The influence of auditory rhythms on the speed of inferred motion.

The present research explored the influence of isochronous auditory rhythms on the timing of movement-related prediction in two experiments. In both experiments, participants observed a moving disc that was visible for a predetermined period before disappearing behind a small, medium, or large occluded area for the remainder of its movement. In Experiment 1, the disc was visible for 1 s. During this period, participants were exposed to either a fast or slow auditory rhythm, or they heard nothing. They were instructed to press a key to indicate when they believed the moving disc had reached a specified location on the other side of the occluded area. The procedure measured the (signed) error in participants' estimate of the time it would take for a moving object to contact a stationary one. The principal results of Experiment 1 were main effects of the rate of the auditory rhythm and of the size of the occlusion on participants' judgments. In Experiment 2, the period of visibility was varied with size of the occlusion area to keep the total movement time constant for all three levels of occlusion. The results replicated the main effect of rhythm found in Experiment 1 and showed a small, significant interaction, but indicated no main effect of occlusion size. Overall, the results indicate that exposure to fast isochronous auditory rhythms during an interval of inferred motion can influence the imagined rate of such motion and suggest a possible role of an internal rhythmicity in the maintenance of temporally accurate dynamic mental representations.

L1cam acts as a modifier gene during enteric nervous system development.

The enteric nervous system is derived from neural crest cells that migrate from the caudal hindbrain and colonise the gut. Failure of neural crest cells to fully colonise the gut results in an "aganglionic zone" that lacks a functional enteric nervous system over a variable length of the distal bowel, a condition in human infants known as Hirschsprung's disease. The variability observed in the penetrance and severity of Hirschsprung's disease suggests a role for modifier genes. Clinical studies have identified a population of Hirschsprung's patients with mutations in L1CAM that also have a common polymorphism in RET, suggesting a possible interaction between L1CAM and RET. Therefore, we examined whether L1cam could interact with Ret, its ligand Gdnf, and a known transcriptional activator of Ret, Sox10. Using a two-locus complementation approach, we show that loss of L1cam in conjunction with a heterozygous loss of Ret or Gdnf did not result in aganglionosis. However, L1cam did interact with Sox10 to significantly increase the incidence of aganglionosis. We show that an interaction between L1cam and Sox10 significantly perturbs neural crest migration within the developing gut, and that neural crest cells undergo excessive cell death prior to gut entry. Finally, we show that Sox10 can regulate the expression of L1cam. Thus, L1cam can act as a modifier gene for the HSCR associated gene, Sox10, and is likely to play a role in the etiology of Hirschsprung's disease.

Small-molecule induction of neural crest-like cells derived from human neural progenitors.

Neural crest (NC) cells are stem cells that are specified within the embryonic neuroectodermal epithelium and migrate to stereotyped peripheral sites for differentiation into many cell types. Several neurocristopathies involve a deficit of NC-derived cells, raising the possibility of stem cell therapy. In Hirschsprung's disease the distal bowel lacks an enteric nervous system caused by a failure of colonization by NC-derived cells. We have developed a robust method of producing migrating NC-like cells from human embryonic stem cell-derived neural progenitors using a coculture system of mouse embryonic fibroblasts. Significantly, subsequent exposure to Y27632, a small-molecule inhibitor of the Rho effectors ROCKI/II, dramatically increased the efficiency of differentiation into NC-like cells, identified by marker expression in vitro. NC-like cells derived by this method were able to migrate along NC pathways in avian embryos in ovo and within explants of murine bowel, and to differentiate into cells with neuronal and glial markers. This is the first study to report the use of a small molecule to induce cells with NC characteristics from embryonic stem cells that can migrate and generate neurons and support cells in complex tissue. Furthermore, this study demonstrates that small-molecule regulators of ROCKI/II signaling may be valuable tools for stem cell research aimed at treatment of neurocristopathies.

Probabilistically Valid Inference of Covariation From a Single x,y Observation When Univariate Characteristics Are Known.

Participants were asked to draw inferences about correlation from single x,y observations. In Experiment 1 statistically sophisticated participants were given the univariate characteristics of distributions of x and y and asked to infer whether a single x, y observation came from a correlated or an uncorrelated population. In Experiment 2, students with a variety of statistical backgrounds assigned posterior probabilities to five possible populations based on single x, y observations, again given knowledge of the univariate statistics. In Experiment 3, statistically naïve participants were given a problem analogous to that given in Experiment 1, framed verbally. Experiment 4 replicated Experiment 3 but added an "impossible to determine" response option. Models that rely on computing sample correlations make no predictions about these investigations. From a Bayesian perspective, participants' inferences in all four experiments tended to make probabilistically valid inferences as long as the single datum was directional. The results are discussed in light of the Brunswikian notion of vicarious functioning.

Effects of NGF, NT-3 and GDNF family members on neurite outgrowth and migration from pelvic ganglia from embryonic and newborn mice.

BACKGROUND: Pelvic ganglia are derived from the sacral neural crest and contain both sympathetic and parasympathetic neurons. Various members of the neurotrophin and GDNF families of neurotrophic factors have been shown to play important roles in the development of a variety of peripheral sympathetic and parasympathetic neurons; however, to date, the role of these factors in the development of pelvic ganglia has been limited to postnatal and older ages. We examined the effects of NGF, NT-3, GDNF, neurturin and artemin on cell migration and neurite outgrowth from explants of the pelvic ganglia from embryonic and newborn mice grown on collagen gels, and correlated the responses with the immunohistochemical localization of the relevant receptors in fixed tissue. RESULTS: Cell migration assays showed that GDNF strongly stimulated migration of tyrosine hydroxylase (TH) cells of pelvic ganglia from E11.5, E14.5 and P0 mice. Other factors also promoted TH cell migration, although to a lesser extent and only at discrete developmental stages. The cells and neurites of the pelvic ganglia were responsive to each of the GDNF family ligands--GDNF, neurturin and artemin--from E11.5 onwards. In contrast, NGF and NT-3 did not elicit a significant neurite outgrowth effect until E14.5 onwards. Artemin and NGF promoted significant outgrowth of sympathetic (TH+) neurites only, whereas neurturin affected primarily parasympathetic (TH-negative) neurite outgrowth, and GDNF and NT-3 enhanced both sympathetic and parasympathetic neurite outgrowth. In comparison, collagen gel assays using gut explants from E11.5 and E14.5 mice showed neurite outgrowth only in response to GDNF at E11.5 and to neurturin only in E14.5 mice. CONCLUSION: Our data show that there are both age-dependent and neuron type-dependent differences in the responsiveness of embryonic and neo-natal pelvic ganglion neurons to growth factors.

Development of satellite glia in mouse sympathetic ganglia: GDNF and GFR alpha 1 are not essential.

The phenotypic development of satellite cells in mouse sympathetic ganglia was examined by localizing the transcription factors, Sox10 and Phox2b, the neuronal marker, tyrosine hydroxylase (TH), and brain-derived fatty acid binding protein (B-FABP), which identifies glial precursors and mature glia. In E10.5 mice, most cells in the sympathetic chain expressed both Sox10 and Phox2b, with a minority of cells expressing Sox10 only or Phox2b only. In E11.5 mice, the majority of cells expressed Sox10 only or Phox2b only. B-FABP was colocalized with Sox10 in satellite glial precursors, which were located on the periphery of the ganglion. There was no overlap between B-FABP and Phox2b or B-FABP and TH. During subsequent development, the number of B-FABP+ cells increased and they became more common deep within the ganglion. In E12.5 and E18.5 mice, there was no overlap between Sox10 and Phox2b, and 98% of Sox10 cells were also B-FABP+. Satellite glial precursors in E11.5-E15.5 mice also expressed the GDNF-binding molecule, GFRalpha1. B-FABP immunoreactive cells did not express Ret or NCAM, two potential signaling molecules for GDNF/GFRalpha1. In E12.5 and E18.5 mice lacking GFRalpha1 or GDNF, the development of B-FABP immunoreactive satellite cells was normal, and hence neither GDNF or GFRalpha1 are essential for the development of satellite glia in sympathetic ganglia.

Sample size and correlational inference.

In 4 studies, the authors examined the hypothesis that the structure of the informational environment makes small samples more informative than large ones for drawing inferences about population correlations. The specific purpose of the studies was to test predictions arising from the signal detection simulations of R. B. Anderson, M. E. Doherty, N. D. Berg, and J. C. Friedrich (2005). The results of a simulation study in the present article confirmed and extended previous theoretical claims (R. B. Anderson et al., 2005) that in a yes/no correlation detection task, small-sample advantages should occur but should be restricted to particular decision conditions. In 3 behavioral studies, participants viewed larger or smaller samples of data pairs and judged whether each sample had been drawn from a population characterized by a zero correlation or from one characterized by a greater-than-zero correlation. Consistent with traditional statistical theory, accuracy tended to be greater for larger than for smaller samples, though there was a small-sample advantage in 1 experimental condition. The results are discussed in relation to alternative theoretical and behavioral paradigms such as those of Y. Kareev (e.g., 2005) and K. Fiedler and Y. Kareev (2006).

The Wnt receptor Ryk is required for Wnt5a-mediated axon guidance on the contralateral side of the corpus callosum.

Ryk (receptor related to tyrosine kinase) has been shown to be a novel Wnt receptor in both Caenorhabditis elegans and Drosophila melanogaster. Recently, Ryk-Wnt interactions were shown to guide corticospinal axons down the embryonic mouse spinal cord. Here we show that, in Ryk-deficient mice, cortical axons project aberrantly across the major forebrain commissure, the corpus callosum. Many mouse mutants have been described in which loss-of-function mutations result in the inability of callosal axons to cross the midline, thereby forming Probst bundles on the ipsilateral side. In contrast, loss of Ryk does not interfere with the ability of callosal axons to cross the midline but impedes their escape from the midline into the contralateral side. Therefore, Ryk(-/-) mice display a novel callosal guidance phenotype. We also show that Wnt5a acts as a chemorepulsive ligand for Ryk, driving callosal axons toward the contralateral hemisphere after crossing the midline. In addition, whereas callosal axons do cross the midline in Ryk(-/-) embryos, they are defasciculated on the ipsilateral side, indicating that Ryk also promotes fasciculation of axons before midline crossing. In summary, this study expands the emerging role for Wnts in axon guidance and identifies Ryk as a key guidance receptor in the establishment of the corpus callosum. Our analysis of Ryk function further advances our understanding of the molecular mechanisms underlying the formation of this important commissure.

Neural crest and the development of the enteric nervous system.

The formation of the enteric nervous system (ENS) is a particularly interesting example of the migratory ability of the neural crest and of the complexity of structures to which neural crest cells contribute. The distance that neural crest cells migrate to colonize the entire length of the gastrointestinal tract exceeds that of any other neural crest cell population. Furthermore, this migration takes a long time--over 25% of the gestation period for mice and around 3 weeks in humans. After colonizing the gut, neural crest-derived cells within the gut wall then differentiate into glial cells plus many different types of neurons, and generate the most complex part of the peripheral nervous system.

Sample size and the detection of correlation--a signal detection account: comment on Kareev (2000) and Juslin and Olsson (2005).

Simulations examined the hypothesis that small samples can provide better grounds for inferring the existence of a population correlation, p, than can large samples. Samples of 5, 7, 10, 15, or 30 data pairs were drawn either from a population with p=0 or from one with p>0. When decision accuracy was assessed independently for each level of the decision criterion, there was a criterion-specific small-sample advantage. For liberal criteria, accuracy was greater for large than for small samples, but for conservative criteria, the opposite result occurred. There was no small-sample advantage when accuracy was measured as the area under a receiver operating characteristic curve or as the posterior probability of a hit. The results show that small-sample advantages can occur, but under limited conditions.

Expression of UNC-5 in the developing Xenopus visual system.

Netrin-1 and its receptors deleted in colorectal cancer (DCC) and neogenin are expressed within the developing visual system and have been implicated in mediating axon guidance and cell migration. However, the expression of the netrin-1 receptor UNC-5 has not yet been addressed. Here we clone Xenopus UNC-5 (XUNC-5) and describe its expression within the developing visual system. Xunc-5 transcripts are expressed within the developing optic vesicles and later become restricted to the dorsal ciliary marginal zone, a site of retinoblast proliferation and differentiation. This highly restricted expression pattern could make XUNC-5 an excellent marker of dorsal retinal precursor cells.

Characterization of lacZ-expressing cells in the gut of embryonic and adult DbetaH-nlacZ mice.

In mice that express lacZ under the control of a human dopamine beta-hydroxylase gene promoter (DbetaH-nlacZ mice), the nuclei of enteric neurons express the transgene, as shown by the presence of beta-galactosidase (beta-gal) staining (Mercer et al. [1991] Neuron 7:703-716). The transgene is also expressed by neural crest-derived cells in the developing gut before their differentiation into neurons or glial cells (Kapur et al. [1992] Development 116:167-175). However, the cell types expressing the DbetaH-nlacZ transgene within the developing and adult gut have not been fully characterized. Whole-mount preparations of embryonic and adult gut were processed for histochemistry or immunohistochemistry to reveal beta-gal plus markers of undifferentiated neural crest cells (in embryos) or enteric neurons (in adults). In embryonic mice, over 90% of undifferentiated neural crest-derived cells (identified using antibodies to p75) were beta-gal(+). Importantly, crest-derived cells at the migratory wavefront were all beta-gal(+). In adult mice, only a subpopulation of enteric neurons was beta-gal(+), while glial cells showed no beta-gal staining. Considerable variation was observed between the small intestine and colon in the proportion of myenteric neurons that showed beta-gal staining. We examined whether known classes of enteric neurons varied in their expression of DbetaH-nlacZ. In the myenteric plexus of the jejunum and colon, large calretinin(+) neurons did not express lacZ, suggesting that the incomplete penetrance of the DbetaH-nlacZ transgene observed in adult mice is not random. We conclude that the DbetaH-nlacZ transgene provides a reliable marker for examining the colonization of the developing gut by neural crest cells. However, in adult mice, there is variation between mice, between gut regions, and between different classes of enteric neurons in the expression of the transgene.

Transplanted progenitors generate functional enteric neurons in the postnatal colon.

Cell therapy has the potential to treat gastrointestinal motility disorders caused by diseases of the enteric nervous system. Many studies have demonstrated that various stem/progenitor cells can give rise to functional neurons in the embryonic gut; however, it is not yet known whether transplanted neural progenitor cells can migrate, proliferate, and generate functional neurons in the postnatal bowel in vivo. We transplanted neurospheres generated from fetal and postnatal intestinal neural crest-derived cells into the colon of postnatal mice. The neurosphere-derived cells migrated, proliferated, and generated neurons and glial cells that formed ganglion-like clusters within the recipient colon. Graft-derived neurons exhibited morphological, neurochemical, and electrophysiological characteristics similar to those of enteric neurons; they received synaptic inputs; and their neurites projected to muscle layers and the enteric ganglia of the recipient mice. These findings show that transplanted enteric neural progenitor cells can generate functional enteric neurons in the postnatal bowel and advances the notion that cell therapy is a promising strategy for enteric neuropathies.

Genetic interactions and modifier genes in Hirschsprung's disease.

Hirschsprung's disease is a congenital disorder that occurs in 1:5000 live births. It is characterised by an absence of enteric neurons along a variable region of the gastrointestinal tract. Hirschsprung's disease is classified as a multigenic disorder, because the same phenotype is associated with mutations in multiple distinct genes. Furthermore, the genetics of Hirschsprung's disease are highly complex and not strictly Mendelian. The phenotypic variability and incomplete penetrance observed in Hirschsprung's disease also suggests the involvement of modifier genes. Here, we summarise the current knowledge of the genetics underlying Hirschsprung's disease based on human and animal studies, focusing on the principal causative genes, their interactions, and the role of modifier genes.