Comparing families of dynamic causal models

Mathematical models of scientific data can be formally compared using Bayesian model evidence. Previous applications in the biological sciences have mainly focussed on model selection in which one first selects the model with the highest evidence and then makes inferences based on the parameters of that model. This “best model” approach is very useful but can become brittle if there are a large number of models to compare, and if different subjects use different models. To overcome this shortcoming we propose the combination of two further approaches: (i) family level inference and (ii) Bayesian model averaging within families. Family level inference removes uncertainty about aspects of model structure other than the characteristic of interest. For example: What are the inputs to the system? Is processing serial or parallel? Is it linear or nonlinear? Is it mediated by a single, crucial connection? We apply Bayesian model averaging within families to provide inferences about parameters that are independent of further assumptions about model structure. We illustrate the methods using Dynamic Causal Models of brain imaging data

Nose profile morphology and accuracy study of nose profile estimation method in Scottish subadult and Indonesian adult populations

This study investigated nose profile morphology and its relationship to the skull in Scottish subadult and Indonesian adult populations, with the aim of improving the accuracy of forensic craniofacial reconstruction. Samples of 86 lateral head cephalograms from Dundee Dental School (mean age, 11.8 years) and 335 lateral head cephalograms from the Universitas Padjadjaran Dental Hospital, Bandung, Indonesia (mean age 24.2 years), were measured. The method of nose profile estimation based on skull morphology previously proposed by Rynn and colleagues in 2010 (FSMP 6:20–34) was tested in this study. Following this method, three nasal aperture-related craniometrics and six nose profile dimensions were measured from the cephalograms. To assess the accuracy of the method, six nose profile dimensions were estimated from the three craniometric parameters using the published method and then compared to the actual nose profile dimensions. In the Scottish subadult population, no sexual dimorphism was evident in the measured dimensions. In contrast, sexual dimorphism of the Indonesian adult population was evident in all craniometric and nose profile dimensions; notably, males exhibited statistically significant larger values than females. The published method by Rynn and colleagues (FSMP 6:20–34, 2010) performed better in the Scottish subadult population (mean difference of maximum, 2.35 mm) compared to the Indonesian adult population (mean difference of maximum, 5.42 mm in males and 4.89 mm in females). In addition, regression formulae were derived to estimate nose profile dimensions based on the craniometric measurements for the Indonesian adult population. The published method is not sufficiently accurate for use on the Indonesian population, so the derived method should be used. The accuracy of the published method by Rynn and colleagues (FSMP 6:20–34, 2010) was sufficiently reliable to be applied in Scottish subadult population

Variation in the Meaning of Alarm Calls in Verreaux’s and Coquerel’s Sifakas (Propithecus verreauxi, P. coquereli)

The comprehension and usage of primate alarm calls appear to be influenced by social learning. Thus, alarm calls provide flexible behavioral mechanisms that may allow animals to develop appropriate responses to locally present predators. To study this potential flexibility, we compared the usage and function of 3 alarm calls common to 2 closely related sifaka species (Propithecus verreauxi and P. coquereli), in each of 2 different populations with different sets of predators. Playback studies revealed that both species in both of their respective populations emitted roaring barks in response to raptors, and playbacks of this call elicited a specific anti-raptor response (look up and climb down). However, in Verreaux’s sifakas, tchi-faks elicited anti-terrestrial predator responses (look down, climb up) in the population with a higher potential predation threat by terrestrial predators, whereas tchi-faks in the other population were associated with nonspecific flight responses. In both populations of Coquerel’s sifakas, tchi-fak playbacks elicited anti-terrestrial predator responses. More strikingly, Verreaux’s sifakas exhibited anti-terrestrial predator responses after playbacks of growls in the population with a higher threat of predation by terrestrial predators, whereas Coquerel’s sifakas in the raptor-dominated habitat seemed to associate growls with a threat by raptors; the 2 other populations of each species associated a mild disturbance with growls. We interpret this differential comprehension and usage of alarm calls as the result of social learning processes that caused changes in signal content in response to changes in the set of predators to which these populations have been exposed since they last shared a common ancestor

Output from VIP cells of the mammalian central clock regulates daily physiological rhythms

The suprachiasmatic nucleus (SCN) circadian clock is critical for optimising daily cycles in mammalian physiology and behaviour. The roles of the various SCN cell types in communicating timing information to downstream physiological systems remain incompletely understood, however. In particular, while vasoactive intestinal polypeptide (VIP) signalling is essential for SCN function and whole animal circadian rhythmicity, the specific contributions of VIP cell output to physiological control remains uncertain. Here we reveal a key role for SCN VIP cells in central clock output. Using multielectrode recording and optogenetic manipulations, we show that VIP neurons provide coordinated daily waves of GABAergic input to target cells across the paraventricular hypothalamus and ventral thalamus, supressing their activity during the mid to late day. Using chemogenetic manipulation, we further demonstrate specific roles for this circuitry in the daily control of heart rate and corticosterone secretion, collectively establishing SCN VIP cells as influential regulators of physiological timing

A proposal for a coordinated effort for the determination of brainwide neuroanatomical connectivity in model organisms at a mesoscopic scale

In this era of complete genomes, our knowledge of neuroanatomical circuitry remains surprisingly sparse. Such knowledge is however critical both for basic and clinical research into brain function. Here we advocate for a concerted effort to fill this gap, through systematic, experimental mapping of neural circuits at a mesoscopic scale of resolution suitable for comprehensive, brain-wide coverage, using injections of tracers or viral vectors. We detail the scientific and medical rationale and briefly review existing knowledge and experimental techniques. We define a set of desiderata, including brain-wide coverage; validated and extensible experimental techniques suitable for standardization and automation; centralized, open access data repository; compatibility with existing resources, and tractability with current informatics technology. We discuss a hypothetical but tractable plan for mouse, additional efforts for the macaque, and technique development for human. We estimate that the mouse connectivity project could be completed within five years with a comparatively modest budget.Comment: 41 page

Delirium and delirium severity predict the trajectory of the Hierarchical Assessment of Balance and Mobility (HABAM) in hospitalised older people: findings from the DECIDE Study

This is the final version. Available on open access from Oxford University Press via the DOI in this recordBackground: Delirium is common, distressing and associated with poor outcomes. Despite this, delirium remains poorly recognised, resulting in worse outcomes. There is an urgent need for methods to objectively assess for delirium. Physical function has been proposed as a potential surrogate marker, but few studies have monitored physical function in the context of delirium. We examined if trajectories of physical function are affected by the presence and severity of delirium in a representative sample of hospitalised participants over 65 years. Methods: During hospital admissions in 2016, we assessed participants from the DECIDE study daily for delirium and physical function, using the Hierarchical Assessment of Balance and Mobility (HABAM). We used linear mixed models to assess the effect of delirium and delirium severity during admission on HABAM trajectory. Results: Of 178 participants, 58 experienced delirium during admission. Median HABAM scores in those with delirium were significantly higher (indicating worse mobility) than those without delirium. Modelling HABAM trajectories, HABAM scores at first assessment were worse in those with delirium than those without, by 0.76 (95% CI: 0.49-1.04) points. Participants with severe delirium experienced a much greater perturbance in their physical function, with an even lower value at first assessment and slower subsequent improvement. Conclusions: Physical function was worse in those with delirium compared to without. This supports the assertion that motor disturbances are a core feature of delirium and monitoring physical function, using a tool such as the HABAM, may have clinical utility as a surrogate marker for delirium and its resolution.Alzheimer’s SocietyMedical Research Council (MRC

A blind accuracy assessment of computer-modeled forensic facial reconstruction using computed tomography data from live subjects.

A computer modeling system for facial reconstruction has been developed that employs a touch-based application to create anatomically accurate facial models focusing on skeletal detail. This article discusses the advantages and disadvantages of the system and illustrates its accuracy and reliability with a blind study using computed tomography (CT) data of living individuals. Three-dimensional models of the skulls of two white North American adults (one male, one female) were imported into the computer system. Facial reconstructions were produced by two practitioners following the Manchester method. Two posters were produced, each including a face pool of five surface model images and the facial reconstruction. The face pool related to the sex, age, and ethnic group of the target individual and included the surface model image of the target individual. Fifty-two volunteers were asked to choose the face from the face pool that most resembled each reconstruction. Both reconstructions received majority percentage hit rates that were at least 50% greater than any other face in the pool. The combined percentage hit rate was 50% above chance (70%). A quantitative comparison of the facial morphology between the facial reconstructions and the CT scan models of the subjects was carried out using Rapidform(™) 2004 PP2-RF4. The majority of the surfaces of the facial reconstructions showed less than 2.5 mm error and 90% of the male face and 75% of the female face showed less than 5 mm error. Many of the differences between the facial reconstructions and the facial scans were probably the result of positional effects caused during the CT scanning procedure, especially on the female subject who had a fatter face than the male subject. The areas of most facial reconstruction error were at the ears and nasal tip

Aptamer-based multiplexed proteomic technology for biomarker discovery

Interrogation of the human proteome in a highly multiplexed and efficient manner remains a coveted and challenging goal in biology. We present a new aptamer-based proteomic technology for biomarker discovery capable of simultaneously measuring thousands of proteins from small sample volumes (15 [mu]L of serum or plasma). Our current assay allows us to measure ~800 proteins with very low limits of detection (1 pM average), 7 logs of overall dynamic range, and 5% average coefficient of variation. This technology is enabled by a new generation of aptamers that contain chemically modified nucleotides, which greatly expand the physicochemical diversity of the large randomized nucleic acid libraries from which the aptamers are selected. Proteins in complex matrices such as plasma are measured with a process that transforms a signature of protein concentrations into a corresponding DNA aptamer concentration signature, which is then quantified with a DNA microarray. In essence, our assay takes advantage of the dual nature of aptamers as both folded binding entities with defined shapes and unique sequences recognizable by specific hybridization probes. To demonstrate the utility of our proteomics biomarker discovery technology, we applied it to a clinical study of chronic kidney disease (CKD). We identified two well known CKD biomarkers as well as an additional 58 potential CKD biomarkers. These results demonstrate the potential utility of our technology to discover unique protein signatures characteristic of various disease states. More generally, we describe a versatile and powerful tool that allows large-scale comparison of proteome profiles among discrete populations. This unbiased and highly multiplexed search engine will enable the discovery of novel biomarkers in a manner that is unencumbered by our incomplete knowledge of biology, thereby helping to advance the next generation of evidence-based medicine

No cold dust within the supernova remnant Cassiopeia A

A large amount (about three solar masses) of cold (18 K) dust in the prototypical type II supernova remnant Cassiopeia A was recently reported. It was concluded that dust production in type II supernovae can explain how the large quantities (10^8 solar masses) of dust observed in the most distant quasars could have been produced within only 700 million years after the Big Bang. Foreground clouds of interstellar material, however, complicate the interpretation of the earlier submillimetre observations of Cas A. Here we report far-infrared and molecular line observations that demonstrate that most of the detected submillimetre emission originates from interstellar dust in a molecular cloud complex located in the line of sight between the Earth and Cas A, and is therefore not associated with the remnant. The argument that type II supernovae produce copious amounts of dust is not supported by the case of Cas A, which previously appeared to provide the best evidence for this possibility.Comment: 13 pages, 3 figure