TRAJECTORY CLUSTERING USING LATENT CLASS MODELS FOR UNSUPERVISED TBI BIOMARKER TEMPORAL PHENOTYPE DISCOVER

Background: TBI biomarkers display population-level time-varying kinetics [1] which may be a rich source of pathobiological information [2]. At an individual level, deviations from stereotypical trajectories may represent different pathological processes or secondary insults. A method for discovering such phenotypes may be useful in in- dividualising treatments in real-time. Methods: Serial blood (12hourly) and CSF (6hourly) samples were obtained from seventeen adult patients with severe TBI (Stockholm ethics committee approval #2009/1112-31). S100B and neuron-specific enolase (NSE) concentrations were measured along with blood:CSF albumin quotient Qa as a measure of blood-brain-barrier (BBB) integrity. S100B and NSE concentrations were log-transformed: Equivalent to the assumption of baseline exponential decay. We used trajectory modeling combining a quadratic mixed effects model with latent group analysis to search for characteristic trajectories in the measured parameter. Results: For serum S100B, we discovered two phenotypes with fast and slow kinetics. The fast group corresponded with patients with more severe extracranial injury. For serum NSE, again two phenotypes were discovered; a time-decaying group and another with a peak around day 4. CSF analysis yielded two latent groups for both S100B and NSE: a time-decaying group and another displaying prolonged elevation over several days. Qa data clustered into three groups: two with fast, slow decay and another with prolonged elevation. The group with prolonged BBB permeability had corresponding poorer outcomes. Conclusions: Small numbers prevent statistical comparison, but trajectory modeling identified a number of phenotypes with plausible pathobiological significance. In particular the technique revealed a group of patients with secondary serum NSE release and another with sustained BBB permeability. Such groups seem to relate to injury profile and outcome suggesting biological relevance. To our knowledge this is the first use of an unsupervised clustering technique in kinetic phenotype discovery. References: [1] Ercole A, Thelin EP, Holst A, Bellander BM, Nelson DW. Kinetic modelling of serum S100b after traumatic brain injury. BMC Neurol. 2016;16:93. [2] Thelin EP, Zeiler FA, Ercole A, Mondello S, Büki A, Bellander BM, Helmy A, Menon DK, Nelson DW. Serial Sampling of Serum Protein Biomarkers for Monitoring Human Traumatic Brain Injury Dynamics: A Systematic Review. Front Neurol. 2017;8:300

Transmission Characteristics of Primate Vocalizations: Implications for Acoustic Analyses

Acoustic analyses have become a staple method in field studies of animal vocal communication, with nearly all investigations using computer-based approaches to extract specific features from sounds. Various algorithms can be used to extract acoustic variables that may then be related to variables such as individual identity, context or reproductive state. Habitat structure and recording conditions, however, have strong effects on the acoustic structure of sound signals. The purpose of this study was to identify which acoustic parameters reliably describe features of propagated sounds. We conducted broadcast experiments and examined the influence of habitat type, transmission height, and re-recording distance on the validity (deviation from the original sound) and reliability (variation within identical recording conditions) of acoustic features of different primate call types. Validity and reliability varied independently of each other in relation to habitat, transmission height, and re-recording distance, and depended strongly on the call type. The smallest deviations from the original sounds were obtained by a visually-controlled calculation of the fundamental frequency. Start- and end parameters of a sound were most susceptible to degradation in the environment. Because the recording conditions can have appreciable effects on acoustic parameters, it is advisable to validate the extraction method of acoustic variables from recordings over longer distances before using them in acoustic analyses

Quantifying resilience of humans and other animals

All life requires the capacity to recover from challenges that are as inevitable as they are unpredictable. Understanding this resilience is essential for managing the health of humans and their livestock. It has long been difficult to quantify resilience directly, forcing practitioners to rely on indirect static indicators of health. However, measurements from wearable electronics and other sources now allow us to analyze the dynamics of physiology and behavior with unsurpassed resolution. The resulting flood of data coincides with the emergence of novel analytical tools for estimating resilience from the pattern of micro-recoveries observed in natural time series. Such dynamic indicators of resilience (DIORs) may be used to monitor the risk of systemic failure across systems ranging from organs to entire organisms. These tools invite a fundamental rethink of our approach to the adaptive management of health and resilience

Power Analysis in Health Policy and Systems Research: a Guide to Research Conceptualisation

Power is a growing area of study for researchers and practitioners working in the field of health policy and systems research (HPSR). Theoretical development and empirical research on power are crucial for providing deeper, more nuanced understandings of the mechanisms and structures leading to social inequities and health disparities; placing contemporary policy concerns in a wider historical, political and social context; and for contributing to the (re)design or reform of health systems to drive progress towards improved health outcomes. Nonetheless, explicit analyses of power in HPSR remain relatively infrequent, and there are no comprehensive resources that serve as theoretical and methodological starting points. This paper aims to fill this gap by providing a consolidated guide to researchers wishing to consider, design and conduct power analyses of health policies or systems. This practice article presents a synthesis of theoretical and conceptual understandings of power; describes methodologies and approaches for conducting power analyses; discusses how they might be appropriately combined; and throughout reflects on the importance of engaging with positionality through reflexive praxis. Expanding research on power in health policy and systems will generate key insights needed to address underlying drivers of health disparities and strengthen health systems for all

Cuticular Compounds Bring New Insight in the Post-Glacial Recolonization of a Pyrenean Area: Deutonura deficiens Deharveng, 1979 Complex, a Case Study

Background: In most Arthropod groups, the study of systematics and evolution rely mostly on neutral characters, in this context cuticular compounds, as non-neutral characters, represent an underexplored but potentially informative type of characters at the infraspecific level as they have been routinely proven to be involved in sexual attraction. Methods and Findings: The collembolan species complex Deutonura deficiens was chosen as a model in order to test the utility of these characters for delineating four infraspecific entities of this group. Specimens were collected for three subspecies (D. d. deficiens, D. d. meridionalis, D. d. sylvatica) and two morphotypes (D. d. sylvatica morphoype A and B) of the complex; an additional species D. monticola was added. Cuticular compounds were extracted and separated by gas chromatography for each individual. Our results demonstrate that cuticular compounds succeeded in separating the different elements of this complex. Those data allowed also the reconstruction of the phylogenetic relationships among them. Conclusions: The discriminating power of cuticular compounds is directly related to their involvement in sexual attraction and mate recognition. These findings allowed a discussion on the potential involvement of intrinsic and paleoclimatic factors in the origin and the diversification of this complex in the Pyrenean zone. This character type brings the first advanc

Design and baseline characteristics of the ParkFit study, a randomized controlled trial evaluating the effectiveness of a multifaceted behavioral program to increase physical activity in Parkinson patients

<p>Abstract</p> <p>Background</p> <p>Many patients with Parkinson's disease (PD) lead a sedentary lifestyle. Promotion of physical activities may beneficially affect the clinical presentation of PD, and perhaps even modify the course of PD. However, because of physical and cognitive impairments, patients with PD require specific support to increase their level of physical activity.</p> <p>Methods</p> <p>We developed the ParkFit Program: a PD-specific and multifaceted behavioral program to promote physical activity. The emphasis is on creating a behavioral change, using a combination of accepted behavioral motivation techniques. In addition, we designed a multicentre randomized clinical trial to investigate whether this ParkFit Program increases physical activity levels over two years in sedentary PD patients. We intended to include 700 sedentary patients. Primary endpoint is the time spent on physical activities per week, which will be measured every six months using an interview-based 7-day recall.</p> <p>Results</p> <p>In total 3453 PD patients were invited to participate. Ultimately, 586 patients - with a mean (SD) age of 64.1 (7.6) years and disease duration of 5.3 (4.5) years - entered the study. Study participants were younger, had a shorter disease duration and were less sedentary compared with eligible PD patients not willing to participate.</p> <p>Discussion</p> <p>The ParkFit trial is expected to yield important new evidence about behavioral interventions to promote physical activity in sedentary patients with PD. The results of the trial are expected in 2012.</p> <p>Trial registration</p> <p><url>http://clinicaltrials.gov</url> (nr NCT00748488).</p

Exome-chip meta-analysis identifies novel loci associated with cardiac conduction, including ADAMTS6.

BACKGROUND: Genome-wide association studies conducted on QRS duration, an electrocardiographic measurement associated with heart failure and sudden cardiac death, have led to novel biological insights into cardiac function. However, the variants identified fall predominantly in non-coding regions and their underlying mechanisms remain unclear. RESULTS: Here, we identify putative functional coding variation associated with changes in the QRS interval duration by combining Illumina HumanExome BeadChip genotype data from 77,898 participants of European ancestry and 7695 of African descent in our discovery cohort, followed by replication in 111,874 individuals of European ancestry from the UK Biobank and deCODE cohorts. We identify ten novel loci, seven within coding regions, including ADAMTS6, significantly associated with QRS duration in gene-based analyses. ADAMTS6 encodes a secreted metalloprotease of currently unknown function. In vitro validation analysis shows that the QRS-associated variants lead to impaired ADAMTS6 secretion and loss-of function analysis in mice demonstrates a previously unappreciated role for ADAMTS6 in connexin 43 gap junction expression, which is essential for myocardial conduction. CONCLUSIONS: Our approach identifies novel coding and non-coding variants underlying ventricular depolarization and provides a possible mechanism for the ADAMTS6-associated conduction changes.BH

Discovery of novel heart rate-associated loci using the Exome Chip

Resting heart rate is a heritable trait, and an increase in heart rate is associated with increased mortality risk. Genome-wide association study analyses have found loci associated with resting heart rate, at the time of our study these loci explained 0.9% of the variation. This study aims to discover new genetic loci associated with heart rate from Exome Chip meta-analyses. Heart rate was measured from either elecrtrocardiograms or pulse recordings. We meta-analysed heart rate association results from 104 452 European-ancestry individuals from 30 cohorts, genotyped using the Exome Chip. Twenty-four variants were selected for follow-up in an independent dataset (UK Biobank, N = 134 251). Conditional and gene-based testing was undertaken, and variants were investigated with bioinformatics methods. We discovered five novel heart rate loci, and one new independent low-frequency non-synonymous variant in an established heart rate locus (KIAA1755). Lead variants in four of the novel loci are non-synonymous variants in the genes C10orf71, DALDR3, TESK2 and SEC31B. The variant at SEC31B is significantly associated with SEC31B expression in heart and tibial nerve tissue. Further candidate genes were detected from long-range regulatory chromatin interactions in heart tissue (SCD, SLF2 and MAPK8). We observed significant enrichment in DNase I hypersensitive sites in fetal heart and lung. Moreover, enrichment was seen for the first time in human neuronal progenitor cells (derived from embryonic stem cells) and fetal muscle samples by including our novel variants. Our findings advance the knowledge of the genetic architecture of heart rate, and indicate new candidate genes for follow-up functional studies